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1.
Biol Direct ; 19(1): 55, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38978100

RESUMO

Ubiquitinylation of protein substrates results in various but distinct biological consequences, among which ubiquitin-mediated degradation is most well studied for its therapeutic application. Accordingly, artificially targeted ubiquitin-dependent degradation of various proteins has evolved into the therapeutically relevant PROTAC technology. This tethered ubiquitinylation of various targets coupled with a broad assortment of modifying E3 ubiquitin ligases has been made possible by rational design of bi-specific chimeric molecules that bring these proteins in proximity. However, forced ubiquitinylation inflicted by the binary warheads of a chimeric PROTAC molecule should not necessarily result in protein degradation but can be used to modulate other cellular functions. In this respect it should be noted that the ubiquitinylation of a diverse set of proteins is known to control their transport, transcriptional activity, and protein-protein interactions. This review provides examples of potential PROTAC usage based on non-degradable ubiquitinylation.


Assuntos
Proteólise , Ubiquitina-Proteína Ligases , Ubiquitina , Ubiquitinação , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Humanos
2.
Proc Natl Acad Sci U S A ; 121(28): e2322972121, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38968116

RESUMO

Rapid accumulation of repair factors at DNA double-strand breaks (DSBs) is essential for DSB repair. Several factors involved in DSB repair have been found undergoing liquid-liquid phase separation (LLPS) at DSB sites to facilitate DNA repair. RNF168, a RING-type E3 ubiquitin ligase, catalyzes H2A.X ubiquitination for recruiting DNA repair factors. Yet, whether RNF168 undergoes LLPS at DSB sites remains unclear. Here, we identified K63-linked polyubiquitin-triggered RNF168 condensation which further promoted RNF168-mediated DSB repair. RNF168 formed liquid-like condensates upon irradiation in the nucleus while purified RNF168 protein also condensed in vitro. An intrinsically disordered region containing amino acids 460-550 was identified as the essential domain for RNF168 condensation. Interestingly, LLPS of RNF168 was significantly enhanced by K63-linked polyubiquitin chains, and LLPS largely enhanced the RNF168-mediated H2A.X ubiquitination, suggesting a positive feedback loop to facilitate RNF168 rapid accumulation and its catalytic activity. Functionally, LLPS deficiency of RNF168 resulted in delayed recruitment of 53BP1 and BRCA1 and subsequent impairment in DSB repair. Taken together, our finding demonstrates the pivotal effect of LLPS in RNF168-mediated DSB repair.


Assuntos
Quebras de DNA de Cadeia Dupla , Reparo do DNA , Proteína 1 de Ligação à Proteína Supressora de Tumor p53 , Ubiquitina-Proteína Ligases , Ubiquitinação , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Humanos , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/genética , Ubiquitina/metabolismo , Histonas/metabolismo , Histonas/genética , Poliubiquitina/metabolismo
3.
Sci Rep ; 14(1): 15133, 2024 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956194

RESUMO

The goal of this study was to evaluate the intensity of autophagy and ubiquitin-dependent proteolysis processes occurring in myocardium of left ventricle (LV) in subsequent stages of pulmonary arterial hypertension (PAH) to determine mechanisms responsible for LV mass loss in a monocrotaline-induced PAH rat model. LV myocardium samples collected from 32 Wistar rats were analyzed in an early PAH group (n = 8), controls time-paired (n = 8), an end-stage PAH group (n = 8), and their controls (n = 8). Samples were subjected to histological analyses with immunofluorescence staining, autophagy assessment by western blotting, and evaluation of ubiquitin-dependent proteolysis in the LV by immunoprecipitation of ubiquitinated proteins. Echocardiographic, hemodynamic, and heart morphometric parameters were assessed regularly throughout the experiment. Considerable morphological and hemodynamic remodeling of the LV was observed over the course of PAH. The end-stage PAH was associated with significantly impaired LV systolic function and a decrease in LV mass. The LC3B-II expression in the LV was significantly higher in the end-stage PAH group compared to the early PAH group (p = 0.040). The measured LC3B-II/LC3B-I ratios in the end-stage PAH group were significantly elevated compared to the controls (p = 0.039). Immunofluorescence staining showed a significant increase in the abundance of LC3 puncta in the end-stage PAH group compared to the matched controls. There were no statistically significant differences in the levels of expression of all ubiquitinated proteins when comparing both PAH groups and matched controls. Autophagy may be considered as the mechanism behind the LV mass loss at the end stage of PAH.


Assuntos
Autofagia , Ventrículos do Coração , Proteólise , Hipertensão Arterial Pulmonar , Ratos Wistar , Ubiquitina , Animais , Ubiquitina/metabolismo , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Ratos , Masculino , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/patologia , Modelos Animais de Doenças , Miocárdio/metabolismo , Miocárdio/patologia , Ecocardiografia , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Remodelação Ventricular
4.
Cell Mol Life Sci ; 81(1): 271, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38888668

RESUMO

Cystic Fibrosis (CF) is a genetic disease caused by mutations in CFTR gene expressing the anion selective channel CFTR located at the plasma membrane of different epithelial cells. The most commonly investigated variant causing CF is F508del. This mutation leads to structural defects in the CFTR protein, which are recognized by the endoplasmic reticulum (ER) quality control system. As a result, the protein is retained in the ER and degraded via the ubiquitin-proteasome pathway. Although blocking ubiquitination to stabilize the CFTR protein has long been considered a potential pharmacological approach in CF, progress in this area has been relatively slow. Currently, no compounds targeting this pathway have entered clinical trials for CF. On the other hand, the emergence of Orkambi initially, and notably the subsequent introduction of Trikafta/Kaftrio, have demonstrated the effectiveness of molecular chaperone-based therapies for patients carrying the F508del variant and even showed efficacy against other variants. These treatments directly target the CFTR variant protein without interfering with cell signaling pathways. This review discusses the limits and potential future of targeting protein ubiquitination in CF.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Ubiquitinação , Fibrose Cística/metabolismo , Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Fibrose Cística/patologia , Humanos , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Retículo Endoplasmático/metabolismo , Animais , Mutação , Ubiquitina/metabolismo
5.
Cells ; 13(11)2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38891087

RESUMO

Ubiquitin-specific protease 14 (USP14), one of the three major proteasome-associated deubiquitinating enzymes (DUBs), is known to be activated by the AKT-mediated phosphorylation at Ser432. Thereby, AKT can regulate global protein degradation by controlling the ubiquitin-proteasome system (UPS). However, the exact molecular mechanism of USP14 activation by AKT phosphorylation at the atomic level remains unknown. By performing the molecular dynamics (MD) simulation of the USP14 catalytic domain at three different states (inactive, active, and USP14-ubiquitin complex), we characterized the change in structural dynamics by phosphorylation. We observed that the Ser432 phosphorylation induced substantial conformational changes of USP14 in the blocking loop (BL) region to fold it from an open loop into a ß-sheet, which is critical for USP14 activation. Furthermore, phosphorylation also increased the frequency of critical hydrogen bonding and salt bridge interactions between USP14 and ubiquitin, which is essential for DUB activity. Structural dynamics insights from this study pinpoint the important local conformational landscape of USP14 by the phosphorylation event, which would be critical for understanding USP14-mediated proteasome regulation and designing future therapeutics.


Assuntos
Simulação de Dinâmica Molecular , Proteínas Proto-Oncogênicas c-akt , Ubiquitina Tiolesterase , Fosforilação , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Humanos , Ubiquitina/metabolismo , Ativação Enzimática , Domínio Catalítico , Ligação Proteica , Conformação Proteica
6.
Adv Virus Res ; 119: 1-38, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38897707

RESUMO

The ubiquitination process is a reversible posttranslational modification involved in many essential cellular functions, such as innate immunity, cell signaling, trafficking, protein stability, and protein degradation. Viruses can use the ubiquitin system to efficiently enter host cells, replicate and evade host immunity, ultimately enhancing viral pathogenesis. Emerging evidence indicates that enveloped viruses can carry free (unanchored) ubiquitin or covalently ubiquitinated viral structural proteins that can increase the efficiency of viral entry into host cells. Furthermore, viruses continuously evolve and adapt to take advantage of the host ubiquitin machinery, highlighting its importance during virus infection. This review discusses the battle between viruses and hosts, focusing on how viruses hijack the ubiquitination process at different steps of the replication cycle, with a specific emphasis on viral entry. We discuss how ubiquitination of viral proteins may affect tropism and explore emerging therapeutics strategies targeting the ubiquitin system for antiviral drug discovery.


Assuntos
Ubiquitinação , Internalização do Vírus , Replicação Viral , Humanos , Ubiquitina/metabolismo , Vírus/metabolismo , Interações Hospedeiro-Patógeno , Proteínas Virais/metabolismo , Proteínas Virais/genética , Viroses/virologia , Viroses/imunologia , Viroses/metabolismo , Animais , Processamento de Proteína Pós-Traducional
7.
Cell Death Dis ; 15(6): 436, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38902268

RESUMO

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, necessitating the identification of novel therapeutic targets. Lysosome Associated Protein Transmembrane 4B (LAPTM4B) is involved in biological processes critical to cancer progression, such as regulation of solute carrier transporter proteins and metabolic pathways, including mTORC1. However, the metabolic processes governed by LAPTM4B and its role in oncogenesis remain unknown. In this study, we conducted unbiased metabolomic screens to uncover the metabolic landscape regulated by LAPTM4B. We observed common metabolic changes in several knockout cell models suggesting of a role for LAPTM4B in suppressing ferroptosis. Through a series of cell-based assays and animal experiments, we demonstrate that LAPTM4B protects tumor cells from erastin-induced ferroptosis both in vitro and in vivo. Mechanistically, LAPTM4B suppresses ferroptosis by inhibiting NEDD4L/ZRANB1 mediated ubiquitination and subsequent proteasomal degradation of the cystine-glutamate antiporter SLC7A11. Furthermore, metabolomic profiling of cancer cells revealed that LAPTM4B knockout leads to a significant enrichment of ferroptosis and associated metabolic alterations. By integrating results from cellular assays, patient tissue samples, an animal model, and cancer databases, this study highlights the clinical relevance of the LAPTM4B-SLC7A11-ferroptosis signaling axis in NSCLC progression and identifies it as a potential target for the development of cancer therapeutics.


Assuntos
Sistema y+ de Transporte de Aminoácidos , Carcinoma Pulmonar de Células não Pequenas , Ferroptose , Neoplasias Pulmonares , Complexo de Endopeptidases do Proteassoma , Ubiquitina , Ferroptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Animais , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo , Camundongos , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Proteínas Oncogênicas/metabolismo , Proteínas Oncogênicas/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Linhagem Celular Tumoral , Ubiquitinação , Camundongos Nus , Proteólise/efeitos dos fármacos
8.
Sci Adv ; 10(24): eadm8449, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38865459

RESUMO

The accumulation of protein aggregates is a hallmark of many diseases, including Alzheimer's disease. As a major pillar of the proteostasis network, autophagy mediates the degradation of protein aggregates. The autophagy cargo receptor p62 recognizes ubiquitin on proteins and cooperates with TAX1BP1 to recruit the autophagy machinery. Paradoxically, protein aggregates are not degraded in various diseases despite p62 association. Here, we reconstituted the recognition by the autophagy receptors of physiological and pathological Tau forms. Monomeric Tau recruits p62 and TAX1BP1 via the sequential actions of the chaperone and ubiquitylation machineries. In contrast, Tau fibrils from Alzheimer's disease brains are recognized by p62 but fail to recruit TAX1BP1. This failure is due to the masking of fibrils ubiquitin moieties by p62. Tau fibrils are resistant to deubiquitylation, and, thus, this nonproductive interaction of p62 with the fibrils is irreversible. Our results shed light on the mechanism underlying autophagy evasion by protein aggregates and their consequent accumulation in disease.


Assuntos
Autofagia , Proteína Sequestossoma-1 , Ubiquitinação , Proteínas tau , Humanos , Proteínas tau/metabolismo , Proteínas tau/química , Proteína Sequestossoma-1/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Ligação Proteica , Agregados Proteicos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ubiquitina/metabolismo , Proteínas de Neoplasias
9.
Mol Cell ; 84(11): 2011-2013, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38848689

RESUMO

In this issue of Molecular Cell, Yi et al.1 demonstrate that reduced mTORC1 activity induces the CTLH E3 ligase-dependent degradation of HMGCS1, an enzyme in the mevalonate pathway, thus revealing a unique connection between mTORC1 signaling and the degradation of a specific metabolic enzyme via the ubiquitin-proteasome system.


Assuntos
Alvo Mecanístico do Complexo 1 de Rapamicina , Complexo de Endopeptidases do Proteassoma , Transdução de Sinais , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Proteólise , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/genética , Complexos Multiproteicos/metabolismo , Complexos Multiproteicos/genética , Animais , Ácido Mevalônico/metabolismo , Ubiquitina/metabolismo
10.
Int J Mol Med ; 54(2)2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-38940355

RESUMO

The ubiquitin (Ub)­proteasome system (UPS) plays a pivotal role in maintaining protein homeostasis and function to modulate various cellular processes including skeletal cell differentiation and bone homeostasis. The Ub ligase E3 promotes the transfer of Ub to the target protein, especially transcription factors, to regulate the proliferation, differentiation and survival of bone cells, as well as bone formation. In turn, the deubiquitinating enzyme removes Ub from modified substrate proteins to orchestrate bone remodeling. As a result of abnormal regulation of ubiquitination, bone cell differentiation exhibits disorder and then bone homeostasis is affected, consequently leading to osteoporosis. The present review discussed the role and mechanism of UPS in bone remodeling. However, the specific mechanism of UPS in the process of bone remodeling is still not fully understood and further research is required. The study of the mechanism of action of UPS can provide new ideas and methods for the prevention and treatment of osteoporosis. In addition, the most commonly used osteoporosis drugs that target ubiquitination processes in the clinic are discussed in the current review.


Assuntos
Osteoporose , Ubiquitina , Ubiquitinação , Humanos , Osteoporose/metabolismo , Osteoporose/patologia , Animais , Ubiquitina/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Remodelação Óssea , Ubiquitina-Proteína Ligases/metabolismo
11.
Sci Rep ; 14(1): 13037, 2024 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844605

RESUMO

The proteasome-associated deubiquitinase USP14 is a potential drug target. Using an inducible USP14 knockout system in colon cancer cells, we found that USP14 depletion impedes cellular proliferation, induces cell cycle arrest, and leads to a senescence-like phenotype. Transcriptomic analysis revealed altered gene expression related to cell division and cellular differentiation. USP14 knockout cells also exhibited changes in morphology, actin distribution, and expression of actin cytoskeletal components. Increased ubiquitin turnover was observed, offset by upregulation of polyubiquitin genes UBB and UBC. Pharmacological inhibition of USP14 with IU1 increased ubiquitin turnover but did not affect cellular growth or morphology. BioGRID data identified USP14 interactors linked to actin cytoskeleton remodeling, DNA damage repair, mRNA splicing, and translation. In conclusion, USP14 loss in colon cancer cells induces a transient quiescent cancer phenotype not replicated by pharmacologic inhibition of its deubiquitinating activity.


Assuntos
Proliferação de Células , Senescência Celular , Neoplasias Colorretais , Ubiquitina Tiolesterase , Humanos , Senescência Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/genética , Linhagem Celular Tumoral , Fenótipo , Complexo de Endopeptidases do Proteassoma/metabolismo , Pontos de Checagem do Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica , Ubiquitina/metabolismo
12.
Pharmacol Res ; 204: 107215, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38744399

RESUMO

The ubiquitinproteasome system (UPS) is the main mechanism responsible for the intracellular degradation of misfolded or damaged proteins. Under inflammatory conditions, the immunoproteasome, an isoform of the proteasome, can be induced, enhancing the antigen-presenting function of the UPS. Furthermore, the immunoproteasome also serves nonimmune functions, such as maintaining protein homeostasis and regulating signalling pathways, and is involved in the pathophysiological processes of various cardiovascular diseases (CVDs). This review aims to provide a comprehensive summary of the current research on the involvement of the immunoproteasome in cardiovascular diseases, with the ultimate goal of identifying novel strategies for the treatment of these conditions.


Assuntos
Doenças Cardiovasculares , Complexo de Endopeptidases do Proteassoma , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo , Complexo de Endopeptidases do Proteassoma/imunologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/metabolismo , Animais , Ubiquitina/metabolismo , Ubiquitina/imunologia , Transdução de Sinais
13.
Biochim Biophys Acta Rev Cancer ; 1879(4): 189119, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38761982

RESUMO

Tumor recurrence is a mechanism triggered in sparse populations of cancer cells that usually remain in a quiescent state after strict stress and/or therapeutic factors, which is affected by a variety of autocrine and microenvironmental cues. Despite thorough investigations, the biology of dormant and/or cancer stem cells is still not fully elucidated, as for the mechanisms of their reawakening, while only the major molecular patterns driving the relapse process have been identified to date. These molecular patterns profoundly interfere with the elements of cellular proteostasis systems that support the efficiency of the recurrence process. As a major proteostasis machinery, we review the role of the ubiquitin-proteasome system (UPS) in tumor cell dormancy and reawakening, devoting particular attention to the functions of its components, E3 ligases, deubiquitinating enzymes and proteasomes in cancer recurrence. We demonstrate how UPS components functionally or mechanistically interact with the pivotal proteins implicated in the recurrence program and reveal that modulators of the UPS hold promise to become an efficient adjuvant therapy for eradicating refractory tumor cells to impede tumor relapse.


Assuntos
Recidiva Local de Neoplasia , Neoplasias , Complexo de Endopeptidases do Proteassoma , Ubiquitina , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo , Neoplasias/patologia , Neoplasias/metabolismo , Neoplasias/genética , Ubiquitina/metabolismo , Recidiva Local de Neoplasia/patologia , Animais , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/metabolismo , Microambiente Tumoral
14.
Biochem Biophys Res Commun ; 720: 150101, 2024 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-38749191

RESUMO

Poly(ADP-ribose) polymerases (PARPs) are critical to regulating cellular activities, such as the response to DNA damage and cell death. PARPs catalyze a reversible post-translational modification (PTM) in the form of mono- or poly(ADP-ribosyl)ation. This type of modification is known to form a ubiquitin-ADP-ribose (Ub-ADPR) conjugate that depends on the actions of Deltex family of E3 ubiquitin ligases (DTXs). In particular, DTXs add ubiquitin to the 3'-OH of adenosine ribose' in ADP-ribose, which effectively sequesters ubiquitin and impedes ubiquitin-dependent signaling. Previous work demonstrates DTX function for ubiquitination of protein-free ADPR, mono-ADP-ribosylated peptides, and ADP-ribosylated nucleic acids. However, the dynamics of DTX-mediated ubiquitination of poly(ADP-ribosyl)ation remains to be defined. Here we show that the ADPR ubiquitination function is not found in other PAR-binding E3 ligases and is conserved across DTX family members. Importantly, DTXs specifically target poly(ADP-ribose) chains for ubiquitination that can be cleaved by PARG, the primary eraser of poly(ADP-ribose), leaving the adenosine-terminal ADPR unit conjugated to ubiquitin. Our collective results demonstrate the DTXs' specific ubiquitination of the adenosine terminus of poly(ADP-ribosyl)ation and suggest the unique Ub-ADPR conjugation process as a basis for PARP-DTX control of cellular activities.


Assuntos
Adenosina Difosfato Ribose , Ubiquitina-Proteína Ligases , Ubiquitinação , Ubiquitina-Proteína Ligases/metabolismo , Humanos , Adenosina Difosfato Ribose/metabolismo , Poli ADP Ribosilação , Poli Adenosina Difosfato Ribose/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Poli(ADP-Ribose) Polimerases/química , Poli(ADP-Ribose) Polimerases/genética , Ubiquitina/metabolismo , ADP-Ribosilação , Células HEK293
15.
Biochem Soc Trans ; 52(3): 1085-1098, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38716888

RESUMO

In vivo, muscle and neuronal cells are post-mitotic, and their function is predominantly regulated by proteostasis, a multilayer molecular process that maintains a delicate balance of protein homeostasis. The ubiquitin-proteasome system (UPS) is a key regulator of proteostasis. A dysfunctional UPS is a hallmark of muscle ageing and is often impacted in neuromuscular disorders (NMDs). Malfunction of the UPS often results in aberrant protein accumulation which can lead to protein aggregation and/or mis-localization affecting its function. Deubiquitinating enzymes (DUBs) are key players in the UPS, controlling protein turnover and maintaining the free ubiquitin pool. Several mutations in DUB encoding genes are linked to human NMDs, such as ATXN3, OTUD7A, UCHL1 and USP14, whilst other NMDs are associated with dysregulation of DUB expression. USP5, USP9X and USP14 are implicated in synaptic transmission and remodeling at the neuromuscular junction. Mice lacking USP19 show increased maintenance of lean muscle mass. In this review, we highlight the involvement of DUBs in muscle physiology and NMDs, particularly in processes affecting muscle regeneration, degeneration and inflammation following muscle injury. DUBs have recently garnered much respect as promising drug targets, and their roles in muscle maturation, regeneration and degeneration may provide the framework for novel therapeutics to treat muscular disorders including NMDs, sarcopenia and cachexia.


Assuntos
Enzimas Desubiquitinantes , Humanos , Animais , Enzimas Desubiquitinantes/metabolismo , Músculo Esquelético/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo , Doenças Neuromusculares/metabolismo , Doenças Neuromusculares/genética , Doenças Neuromusculares/fisiopatologia , Doenças Neuromusculares/enzimologia , Doenças Musculares/metabolismo , Doenças Musculares/genética , Camundongos , Proteostase
16.
Autophagy ; 20(7): 1471-1472, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38744436

RESUMO

The destination of a damaged lysosome is either being repaired if the damage is small or degraded through a lysosome-specific macroautophagy/autophagy pathway named lysophagy when the damage is too extensive to repair. Even though previous studies report lumenal glycan exposure during lysosome damage as a signal to trigger lysophagy, it is possibly beneficial for cells to initiate lysophagy earlier than membrane rupture. In a recently published article, Gahlot et al. determined that SPART/SPG20 senses lipid-packing defects and recruits and activates the ubiquitin ligase ITCH, which labels damaged lysosomes with ubiquitin chains to initiate lysophagy.


Assuntos
Autofagia , Lisossomos , Lisossomos/metabolismo , Humanos , Autofagia/fisiologia , Animais , Macroautofagia/fisiologia , Ubiquitina-Proteína Ligases/metabolismo , Modelos Biológicos , Ubiquitina/metabolismo
17.
J Biol Chem ; 300(6): 107337, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38705397

RESUMO

APE2 plays important roles in the maintenance of genomic and epigenomic stability including DNA repair and DNA damage response. Accumulating evidence has suggested that APE2 is upregulated in multiple cancers at the protein and mRNA levels and that APE2 upregulation is correlative with higher and lower overall survival of cancer patients depending on tumor type. However, it remains unknown how APE2 protein abundance is maintained and regulated in cells. Here, we provide the first evidence of APE2 regulation via the posttranslational modification ubiquitin. APE2 is poly-ubiquitinated via K48-linked chains and degraded via the ubiquitin-proteasome system where K371 is the key residue within APE2 responsible for its ubiquitination and degradation. We further characterize MKRN3 as the E3 ubiquitin ligase for APE2 ubiquitination in cells and in vitro. In summary, this study offers the first definition of the APE2 proteostasis network and lays the foundation for future studies pertaining to the posttranslational modification regulation and functions of APE2 in genome integrity and cancer etiology/treatment.


Assuntos
DNA Liase (Sítios Apurínicos ou Apirimidínicos) , Ubiquitinação , Humanos , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Ubiquitina/metabolismo , Processamento de Proteína Pós-Traducional , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Células HEK293 , Complexo de Endopeptidases do Proteassoma/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Proteólise , Endonucleases , Enzimas Multifuncionais
18.
J Biol Chem ; 300(6): 107359, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38735474

RESUMO

FOXK2 is a crucial transcription factor implicated in a wide array of biological activities and yet understanding of its molecular regulation at the level of protein turnover is limited. Here, we identify that FOXK2 undergoes degradation in lung epithelia in the presence of the virulent pathogens Pseudomonas aeruginosa and Klebsiella pneumoniae through ubiquitin-proteasomal processing. FOXK2 through its carboxyl terminus (aa 428-478) binds the Skp-Cullin-F-box ubiquitin E3 ligase subunit FBXO24 that mediates multisite polyubiquitylation of the transcription factor resulting in its nuclear degradation. FOXK2 was detected within the mitochondria and targeted depletion of the transcription factor or cellular expression of FOXK2 mutants devoid of key carboxy terminal domains significantly impaired mitochondrial function. In experimental bacterial pneumonia, Fbxo24 heterozygous mice exhibited preserved mitochondrial function and Foxk2 protein levels compared to WT littermates. The results suggest a new mode of regulatory control of mitochondrial energetics through modulation of FOXK2 cellular abundance.


Assuntos
Fatores de Transcrição Forkhead , Mitocôndrias , Animais , Mitocôndrias/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Camundongos , Humanos , Proteólise , Proteínas F-Box/metabolismo , Proteínas F-Box/genética , Proteínas Ligases SKP Culina F-Box/metabolismo , Proteínas Ligases SKP Culina F-Box/genética , Ubiquitinação , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Respiração Celular
19.
Cancer Lett ; 594: 216978, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38795760

RESUMO

Ubiquitination and related cellular processes control a variety of aspects in human cell biology, and defects in these processes contribute to multiple illnesses. In recent decades, our knowledge about the pathological role of ubiquitination in lymphoid cancers and therapeutic strategies to target the modified ubiquitination system has evolved tremendously. Here we review the altered signalling mechanisms mediated by the aberrant expression of cancer-associated E2s/E3s and deubiquitinating enzymes (DUBs), which result in the hyperactivation of oncoproteins or the frequently allied downregulation of tumour suppressors. We discuss recent highlights pertaining to the several different therapeutic interventions which are currently being evaluated to effectively block abnormal ubiquitin-proteasome pathway and the use of heterobifunctional molecules which recruit the ubiquitination system to degrade or stabilize non-cognate substrates. This review aids in comprehension of ubiquitination aberrance in lymphoid cancers and current targeting strategies and elicits further investigations to deeply understand the link between cellular ubiquitination and lymphoid pathogenesis as well as to ameliorate corresponding treatment interventions.


Assuntos
Transdução de Sinais , Ubiquitina , Ubiquitinação , Humanos , Ubiquitina/metabolismo , Animais , Linfoma/metabolismo , Linfoma/tratamento farmacológico , Linfoma/patologia , Terapia de Alvo Molecular , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Enzimas Desubiquitinantes/metabolismo
20.
Plant Physiol Biochem ; 212: 108700, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38781635

RESUMO

Eukaryotic cells have evolved dynamic quality control pathways and recycling mechanisms for cellular homeostasis. We discuss here, the two major systems for quality control, the ubiquitin-proteasome system (UPS) and autophagy that regulate cellular protein and organelle turnover and ensure efficient nutrient management, cellular integrity and long-term wellbeing of the plant. Both the pathways rely on ubiquitination signal to identify the targets for proteasomal and autophagic degradation, yet they use distinct degradation machinery to process these cargoes. Nonetheless, both UPS and autophagy operate together as an interrelated quality control mechanism where they communicate with each other at multiple nodes to coordinate and/or compensate the recycling mechanism particularly under development and environmental cues. Here, we provide an update on the cellular machinery of autophagy and UPS, unravel the nodes of their crosstalk and particularly highlight the factors responsible for their differential deployment towards protein, macromolecular complexes and organelles.


Assuntos
Autofagia , Complexo de Endopeptidases do Proteassoma , Ubiquitina , Complexo de Endopeptidases do Proteassoma/metabolismo , Autofagia/fisiologia , Ubiquitina/metabolismo , Ubiquitinação , Plantas/metabolismo
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