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1.
EMBO Rep ; 25(8): 3651-3677, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39039299

RESUMO

Endoplasmic reticulum (ER) remodeling is vital for cellular organization. ER-phagy, a selective autophagy targeting ER, plays an important role in maintaining ER morphology and function. The FAM134 protein family, including FAM134A, FAM134B, and FAM134C, mediates ER-phagy. While FAM134B mutations are linked to hereditary sensory and autonomic neuropathy in humans, the physiological role of the other FAM134 proteins remains unknown. To address this, we investigate the roles of FAM134 proteins using single and combined knockouts (KOs) in mice. Single KOs in young mice show no major phenotypes; however, combined Fam134b and Fam134c deletion (Fam134b/cdKO), but not the combination including Fam134a deletion, leads to rapid neuromuscular and somatosensory degeneration, resulting in premature death. Fam134b/cdKO mice show rapid loss of motor and sensory axons in the peripheral nervous system. Long axons from Fam134b/cdKO mice exhibit expanded tubular ER with a transverse ladder-like appearance, whereas no obvious abnormalities are present in cortical ER. Our study unveils the critical roles of FAM134C and FAM134B in the formation of tubular ER network in axons of both motor and sensory neurons.


Assuntos
Axônios , Retículo Endoplasmático , Proteínas de Membrana , Animais , Humanos , Camundongos , Axônios/metabolismo , Retículo Endoplasmático/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Knockout
2.
Bone ; 177: 116927, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37797712

RESUMO

Missense variants in the MBTPS2 gene, located on the X chromosome, have been associated with an X-linked recessive form of osteogenesis imperfecta (X-OI), an inherited bone dysplasia characterized by multiple and recurrent bone fractures, short stature, and various skeletal deformities in affected individuals. The role of site-2 protease, encoded by MBTPS2, and the molecular pathomechanism underlying the disease are to date elusive. This study is the first to report on the generation of two Mbtps2 mouse models, a knock-in mouse carrying one of the disease-causative MBTPS2 variants (N455S) and a Mbtps2 knock-out (ko) mouse. Because both loss-of-function variants lead to embryonic lethality in hemizygous male mutant mice, we performed a comprehensive skeletal analysis of heterozygous Mbtps2+/N455S and Mbtps2+/ko female mice. Both models displayed osteochondral abnormalities such as thinned subchondral bone, altered subchondral osteocyte interconnectivity as well as thickened articular cartilage with chondrocyte clustering, altogether resembling an early osteoarthritis (OA) phenotype. However, distant from the joints, no alterations in the bone mass and turnover could be detected in either of the mutant mice. Based on our findings we conclude that MBTPS2 haploinsufficiency results in early OA-like alterations in the articular cartilage and underlying subchondral bone, which likely precede the development of typical OI phenotype in bone. Our study provides first evidence for a potential role of site-2 protease for maintaining homeostasis of both bone and cartilage.


Assuntos
Cartilagem Articular , Osteoartrite , Osteogênese Imperfeita , Camundongos , Masculino , Feminino , Animais , Osteogênese Imperfeita/genética , Osteócitos , Osso e Ossos , Peptídeo Hidrolases
3.
Eur J Cancer ; 190: 112949, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37453241

RESUMO

OBJECTIVE: The aim of this study was to investigate the response rates of different extremity soft-tissue sarcoma subtypes (eSTS) after isolated limb perfusion (ILP), based on an international multi-centre study. MATERIALS AND METHODS: The retrospective cohort comprised eSTS patients from 17 specialised ILP centres that underwent melphalan-based ILP, with or without recombinant human tumour necrosis factor (rhTNFα) (TM-ILP and M-ILP, respectively). Response was measured on imaging (magnetic resonance imaging) and/or clinical response, for which M-ILPs were excluded. RESULTS: A total of 1109 eSTS patients were included. The three most common histological subtypes were undifferentiated pleomorphic sarcoma (17%, n = 184), synovial sarcoma (16%, n = 175) and myxofibrosarcoma (8%, n = 87). rhTNFα was used in 93% (TM-ILP) and resulted in a significantly better overall response rate (ORR, p = 0.031) and complete responses (CR, p < 0.001) in comparison to M-ILP, without significant differences among histological subgroups. The ORR of TM-ILP was 68%, including 17% CR. Also, 80% showed progressive disease. Significantly higher response rates were shown for Kaposi sarcoma (KS) with 42% CR and 96% ORR (both p < 0.001), and significantly higher CR rates for angiosarcoma (AS, 45%, p < 0.001) and clear cell sarcoma (CCS, 31%, p = 0.049). ILP was followed by resection ≤ 6 months in 80% of the patients. The overall limb salvage rate was 88%, without significant differences among histological subgroups, but was significantly higher for ILP responders compared to non-responders (93% versus 76%, p < 0.001). CONCLUSION: ILP resulted in high response and LRS among all eSTS subtypes, however, with significant differences between subtypes with most promising results for KS, AS and CCS.


Assuntos
Sarcoma de Kaposi , Sarcoma , Neoplasias de Tecidos Moles , Adulto , Humanos , Estudos Retrospectivos , Quimioterapia do Câncer por Perfusão Regional/métodos , Sarcoma/patologia , Melfalan/uso terapêutico , Extremidades/patologia , Neoplasias de Tecidos Moles/patologia , Perfusão , Fator de Necrose Tumoral alfa , Antineoplásicos Alquilantes/uso terapêutico
4.
Science ; 380(6649): eabn9257, 2023 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-37289866

RESUMO

Aging is associated with changes in circulating levels of various molecules, some of which remain undefined. We find that concentrations of circulating taurine decline with aging in mice, monkeys, and humans. A reversal of this decline through taurine supplementation increased the health span (the period of healthy living) and life span in mice and health span in monkeys. Mechanistically, taurine reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, decreased DNA damage, and attenuated inflammaging. In humans, lower taurine concentrations correlated with several age-related diseases and taurine concentrations increased after acute endurance exercise. Thus, taurine deficiency may be a driver of aging because its reversal increases health span in worms, rodents, and primates and life span in worms and rodents. Clinical trials in humans seem warranted to test whether taurine deficiency might drive aging in humans.


Assuntos
Envelhecimento , Taurina , Animais , Humanos , Camundongos , Envelhecimento/sangue , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Senescência Celular , Haplorrinos , Longevidade/efeitos dos fármacos , Longevidade/fisiologia , Taurina/sangue , Taurina/deficiência , Taurina/farmacologia , Suplementos Nutricionais , Dano ao DNA/efeitos dos fármacos , Telomerase/metabolismo
5.
Sci Adv ; 8(35): eabo1215, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36044577

RESUMO

Selective degradation of the endoplasmic reticulum (ER) via autophagy (ER-phagy) is initiated by ER-phagy receptors, which facilitate the incorporation of ER fragments into autophagosomes. FAM134 reticulon family proteins (FAM134A, FAM134B, and FAM134C) are ER-phagy receptors with structural similarities and nonredundant functions. Whether they respond differentially to the stimulation of ER-phagy is unknown. Here, we describe an activation mechanism unique to FAM134C during starvation. In fed conditions, FAM134C is phosphorylated by casein kinase 2 (CK2) at critical residues flanking the LIR domain. Phosphorylation of these residues negatively affects binding affinity to the autophagy proteins LC3. During starvation, mTORC1 inhibition limits FAM134C phosphorylation by CK2, hence promoting receptor activation and ER-phagy. Using a novel tool to study ER-phagy in vivo and FAM134C knockout mice, we demonstrated the physiological relevance of FAM134C phosphorylation during starvation-induced ER-phagy in liver lipid metabolism. These data provide a mechanistic insight into ER-phagy regulation and an example of autophagy selectivity during starvation.

6.
Front Med (Lausanne) ; 9: 868474, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35872766

RESUMO

Even though ankle sprains are among the most frequent musculoskeletal injuries seen in emergency departments, management of these injuries continues to lack standardization. Our objective was to carry out an umbrella review of systematic reviews to collect the most effective evidence-based treatments and to point out the state-of-the-art management for this injury. PubMed, Scopus, Web of Science, and the Cochrane library were searched from January 2000 to September 2020. After removing duplicates and applying the eligibility criteria, based on titles and abstracts, 32 studies were screened. At the end of the process, 24 articles were included in this umbrella review with a mean score of 7.7/11 on the AMSTAR quality assessment tool. We found evidence supporting the effectiveness of non-surgical treatment in managing acute ankle sprain; moreover, functional treatment seems to be preferable to immobilization. We also found evidence supporting the use of paracetamol or opioids as effective alternatives to non-steroidal anti-inflammatory drugs to reduce pain. Furthermore, we found evidence supporting the effectiveness of manipulative and supervised exercise therapy to prevent re-injury and restore ankle dorsiflexion.

7.
Curr Opin Cell Biol ; 76: 102084, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35533527

RESUMO

Autophagy of the endoplasmic reticulum (ER), known as ER-phagy, is responsible for the degradation of ER portions by lysosomes. ER-phagy is induced in both physiological and stress conditions to maintain ER homeostasis and protein quality control. ER-phagy receptors and their interactors are key regulators of this process. Transcriptional and post-translational regulation of ER-phagy receptors have emerged as critical mechanisms for the modulation of ER-phagy, providing the first hints to understand how this process responds to the cellular needs. Here, we concisely review the main mechanisms regulating ER-phagy receptors and discuss their potential implications in diseases.


Assuntos
Estresse do Retículo Endoplasmático , Proteínas de Membrana , Autofagia/fisiologia , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Lisossomos/metabolismo , Proteínas de Membrana/metabolismo
8.
EMBO Rep ; 22(9): e52289, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34338405

RESUMO

Degradation of the endoplasmic reticulum (ER) via selective autophagy (ER-phagy) is vital for cellular homeostasis. We identify FAM134A/RETREG2 and FAM134C/RETREG3 as ER-phagy receptors, which predominantly exist in an inactive state under basal conditions. Upon autophagy induction and ER stress signal, they can induce significant ER fragmentation and subsequent lysosomal degradation. FAM134A, FAM134B/RETREG1, and FAM134C are essential for maintaining ER morphology in a LC3-interacting region (LIR)-dependent manner. Overexpression of any FAM134 paralogue has the capacity to significantly augment the general ER-phagy flux upon starvation or ER-stress. Global proteomic analysis of FAM134 overexpressing and knockout cell lines reveals several protein clusters that are distinctly regulated by each of the FAM134 paralogues as well as a cluster of commonly regulated ER-resident proteins. Utilizing pro-Collagen I, as a shared ER-phagy substrate, we observe that FAM134A acts in a LIR-independent manner and compensates for the loss of FAM134B and FAM134C, respectively. FAM134C instead is unable to compensate for the loss of its paralogues. Taken together, our data show that FAM134 paralogues contribute to common and unique ER-phagy pathways.


Assuntos
Proteínas de Membrana , Proteômica , Autofagia/genética , Colágeno , Retículo Endoplasmático/genética , Proteínas de Membrana/genética , Controle de Qualidade
9.
Genet Med ; 23(12): 2369-2377, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34341521

RESUMO

PURPOSE: Pathogenic variants in GNPTAB and GNPTG, encoding different subunits of GlcNAc-1-phosphotransferase, cause mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma. This study aimed to investigate the cellular and molecular bases underlying skeletal abnormalities in patients with MLII and MLIII. METHODS: We analyzed bone biopsies from patients with MLIII alpha/beta or MLIII gamma by undecalcified histology and histomorphometry. The skeletal status of Gnptgko and Gnptab-deficient mice was determined and complemented by biochemical analysis of primary Gnptgko bone cells. The clinical relevance of the mouse data was underscored by systematic urinary collagen crosslinks quantification in patients with MLII, MLIII alpha/beta, and MLIII gamma. RESULTS: The analysis of iliac crest biopsies revealed that bone remodeling is impaired in patients with GNPTAB-associated MLIII alpha/beta but not with GNPTG-associated MLIII gamma. Opposed to Gnptab-deficient mice, skeletal remodeling is not affected in Gnptgko mice. Most importantly, patients with variants in GNPTAB but not in GNPTG exhibited increased bone resorption. CONCLUSION: The gene-specific impact on bone remodeling in human individuals and in mice proposes distinct molecular functions of the GlcNAc-1-phosphotransferase subunits in bone cells. We therefore appeal for the necessity to classify MLIII based on genetic in addition to clinical criteria to ensure appropriate therapy.


Assuntos
Reabsorção Óssea , Mucolipidoses , Transferases (Outros Grupos de Fosfato Substituídos) , Animais , Humanos , Camundongos , Mucolipidoses/genética , Mucolipidoses/patologia , Transferases (Outros Grupos de Fosfato Substituídos)/genética
10.
Sci Rep ; 11(1): 3556, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33574442

RESUMO

Severe skeletal alterations are common symptoms in patients with mucolipidosis type II (MLII), a rare lysosomal storage disorder of childhood. We have previously reported that progressive bone loss in a mouse model for MLII is caused by an increased number of bone-resorbing osteoclasts, which is accompanied by elevated expression of the cytokine interleukin-6 (IL-6) in the bone microenvironment. In the present study we addressed the question, if pharmacological blockade of IL-6 can prevent the low bone mass phenotype of MLII mice. Since the cellular IL-6 response can be mediated by either the membrane-bound (classic signaling) or the soluble IL-6 receptor (trans-signaling), we first performed cell culture assays and found that both pathways can increase osteoclastogenesis. We then crossed MLII mice with transgenic mice expressing the recombinant soluble fusion protein sgp130Fc, which represents a natural inhibitor of IL-6 trans-signaling. By undecalcified histology and bone-specific histomorphometry we found that high circulating sgp130Fc levels do not affect skeletal growth or remodeling in wild-type mice. Most importantly, blockade of IL-6 trans-signaling did neither reduce osteoclastogenesis, nor increase bone mass in MLII mice. Therefore, our data clearly demonstrate that the bone phenotype of MLII mice cannot be corrected by blocking the IL-6 trans-signaling.


Assuntos
Interleucina-6/genética , Mucolipidoses/genética , Osteogênese/genética , Esqueleto/patologia , Animais , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos/genética , Mucolipidoses/patologia , Osteoclastos/metabolismo , Osteoclastos/patologia
11.
Dis Model Mech ; 13(11)2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33023972

RESUMO

Mucolipidosis type III (MLIII) gamma is a rare inherited lysosomal storage disorder caused by mutations in GNPTG encoding the γ-subunit of GlcNAc-1-phosphotransferase, the key enzyme ensuring proper intracellular location of multiple lysosomal enzymes. Patients with MLIII gamma typically present with osteoarthritis and joint stiffness, suggesting cartilage involvement. Using Gnptg knockout (Gnptgko ) mice as a model of the human disease, we showed that missorting of a number of lysosomal enzymes is associated with intracellular accumulation of chondroitin sulfate in Gnptgko chondrocytes and their impaired differentiation, as well as with altered microstructure of the cartilage extracellular matrix (ECM). We also demonstrated distinct functional and structural properties of the Achilles tendons isolated from Gnptgko and Gnptab knock-in (Gnptabki ) mice, the latter displaying a more severe phenotype resembling mucolipidosis type II (MLII) in humans. Together with comparative analyses of joint mobility in MLII and MLIII patients, these findings provide a basis for better understanding of the molecular reasons leading to joint pathology in these patients. Our data suggest that lack of GlcNAc-1-phosphotransferase activity due to defects in the γ-subunit causes structural changes within the ECM of connective and mechanosensitive tissues, such as cartilage and tendon, and eventually results in functional joint abnormalities typically observed in MLIII gamma patients. This idea was supported by a deficit of the limb motor function in Gnptgko mice challenged on a rotarod under fatigue-associated conditions, suggesting that the impaired motor performance of Gnptgko mice was caused by fatigue and/or pain at the joint.This article has an associated First Person interview with the first author of the paper.


Assuntos
Cartilagem/patologia , Homeostase , Articulações/patologia , Mucolipidoses/metabolismo , Mucolipidoses/patologia , Tendão do Calcâneo/patologia , Tendão do Calcâneo/ultraestrutura , Envelhecimento/patologia , Animais , Cartilagem/ultraestrutura , Diferenciação Celular , Condrócitos/metabolismo , Condrócitos/patologia , Condrócitos/ultraestrutura , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Matriz Extracelular/ultraestrutura , Colágenos Fibrilares/metabolismo , Lisossomos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora , Mucolipidoses/fisiopatologia , Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo
12.
J Am Soc Nephrol ; 31(8): 1796-1814, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641396

RESUMO

BACKGROUND: The mechanisms balancing proteostasis in glomerular cells are unknown. Mucolipidosis (ML) II and III are rare lysosomal storage disorders associated with mutations of the Golgi-resident GlcNAc-1-phosphotransferase, which generates mannose 6-phosphate residues on lysosomal enzymes. Without this modification, lysosomal enzymes are missorted to the extracellular space, which results in lysosomal dysfunction of many cell types. Patients with MLII present with severe skeletal abnormalities, multisystemic symptoms, and early death; the clinical course in MLIII is less progressive. Despite dysfunction of a major degradative pathway, renal and glomerular involvement is rarely reported, suggesting organ-specific compensatory mechanisms. METHODS: MLII mice were generated and compared with an established MLIII model to investigate the balance of protein synthesis and degradation, which reflects glomerular integrity. Proteinuria was assessed in patients. High-resolution confocal microscopy and functional assays identified proteins to deduce compensatory modes of balancing proteostasis. RESULTS: Patients with MLII but not MLIII exhibited microalbuminuria. MLII mice showed lysosomal enzyme missorting and several skeletal alterations, indicating that they are a useful model. In glomeruli, both MLII and MLIII mice exhibited reduced levels of lysosomal enzymes and enlarged lysosomes with abnormal storage material. Nevertheless, neither model had detectable morphologic or functional glomerular alterations. The models rebalance proteostasis in two ways: MLII mice downregulate protein translation and increase the integrated stress response, whereas MLIII mice upregulate the proteasome system in their glomeruli. Both MLII and MLIII downregulate the protein complex mTORC1 (mammalian target of rapamycin complex 1) signaling, which decreases protein synthesis. CONCLUSIONS: Severe lysosomal dysfunction leads to microalbuminuria in some patients with mucolipidosis. Mouse models indicate distinct compensatory pathways that balance proteostasis in MLII and MLIII.


Assuntos
Glomérulos Renais/metabolismo , Mucolipidoses/metabolismo , Proteinúria/prevenção & controle , Proteostase/fisiologia , Albuminúria/etiologia , Animais , Nitrogênio da Ureia Sanguínea , Células Cultivadas , Modelos Animais de Doenças , Humanos , Lisossomos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mucolipidoses/complicações , Complexo de Endopeptidases do Proteassoma/fisiologia
13.
Toxins (Basel) ; 11(8)2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31349572

RESUMO

Cyanobacteria are a diverse group of photosynthetic Gram-negative bacteria that produce an array of secondary compounds with selective bioactivity against a broad spectrum of organisms and cell lines. In this study, 29 strains isolated from freshwaters in Greece were classified using a polyphasic approach and assigned to Chroococcales, Synechococcales, and Nostocales, representing 11 genera and 17 taxa. There were good agreements between 16S ribosomal RNA (rRNA)-cpcBA-internal genetic spacer (IGS) characterization and morphological features, except for the Jaaginema-Limnothrix group which appears intermixed and needs further elucidation. Methanol extracts of the strains were analyzed for cyanotoxin production and tested against pathogenic bacteria species and several cancer cell lines. We report for the first time a Nostoc oryzae strain isolated from rice fields capable of producing microcystins (MCs) and a Chlorogloeopsis fritschii strain isolated from the plankton of a lake, suggesting that this species may also occur in freshwater temperate habitats. Strains with very high or identical 16S rRNA gene sequences displayed different antibacterial and cytotoxic activities. Extracts from Synechococcus cf. nidulans showed the most potent antibacterial activity against Staphylococcus aureus, whereas Jaaginema sp. strains exhibited potent cytotoxic activities against human colorectal adenocarcinoma and hepatocellular carcinoma cells. Jaaginema Thessaloniki Aristotle University Microalgae and Cyanobacteria (TAU-MAC) 0110 and 0210 strains caused pronounced changes in the actin network and triggered the formation of numerous lipid droplets in hepatocellular carcinoma and green monkey kidney cells, suggesting oxidative stress and/or mitochondrial damage leading to apoptosis.


Assuntos
Toxinas Bacterianas/análise , Cianobactérias/isolamento & purificação , Animais , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Biodiversidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Misturas Complexas/farmacologia , Cianobactérias/classificação , Cianobactérias/genética , Água Doce/microbiologia , Grécia , Humanos , Microalgas/classificação , Microalgas/genética , Microalgas/isolamento & purificação , Filogenia , RNA Ribossômico 16S
14.
Mol Cell Proteomics ; 17(8): 1612-1626, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29773673

RESUMO

Targeting of soluble lysosomal enzymes requires mannose 6-phosphate (M6P) signals whose formation is initiated by the hexameric N-acetylglucosamine (GlcNAc)-1-phosphotransferase complex (α2ß2γ2). Upon proteolytic cleavage by site-1 protease, the α/ß-subunit precursor is catalytically activated but the functions of γ-subunits (Gnptg) in M6P modification of lysosomal enzymes are unknown. To investigate this, we analyzed the Gnptg expression in mouse tissues, primary cultured cells, and in Gnptg reporter mice in vivo, and found high amounts in the brain, eye, kidney, femur, vertebra and fibroblasts. Consecutively we performed comprehensive quantitative lysosomal proteome and M6P secretome analysis in fibroblasts of wild-type and Gnptgko mice mimicking the lysosomal storage disorder mucolipidosis III. Although the cleavage of the α/ß-precursor was not affected by Gnptg deficiency, the GlcNAc-1-phosphotransferase activity was significantly reduced. We purified lysosomes and identified 29 soluble lysosomal proteins by SILAC-based mass spectrometry exhibiting differential abundance in Gnptgko fibroblasts which was confirmed by Western blotting and enzymatic activity analysis for selected proteins. A subset of these lysosomal enzymes show also reduced M6P modifications, fail to reach lysosomes and are secreted, among them α-l-fucosidase and arylsulfatase B. Low levels of these enzymes correlate with the accumulation of non-degraded fucose-containing glycostructures and sulfated glycosaminoglycans in Gnptgko lysosomes. Incubation of Gnptgko fibroblasts with arylsulfatase B partially rescued glycosaminoglycan storage. Combinatorial treatments with other here identified missorted enzymes of this degradation pathway might further correct glycosaminoglycan accumulation and will provide a useful basis to reveal mechanisms of selective, Gnptg-dependent formation of M6P residues on lysosomal proteins.


Assuntos
Enzimas/metabolismo , Lisossomos/metabolismo , Mucolipidoses/metabolismo , Mucolipidoses/patologia , Proteoma/metabolismo , Animais , Embrião de Mamíferos/citologia , Fibroblastos/metabolismo , Glicosaminoglicanos/metabolismo , Humanos , Marcação por Isótopo , Manosefosfatos/metabolismo , Camundongos Knockout , Subunidades Proteicas/metabolismo , Proteólise , Especificidade por Substrato
15.
Biochim Biophys Acta Mol Cell Res ; 1864(11 Pt B): 2162-2168, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28693924

RESUMO

The Golgi-resident site-1 protease (S1P) is a key regulator of cholesterol homeostasis and ER stress responses by converting latent transcription factors sterol regulatory element binding proteins (SREPBs) and activating transcription factor 6 (ATF6), as well as viral glycoproteins to their active forms. S1P is also essential for lysosome biogenesis via proteolytic activation of the hexameric GlcNAc-1-phosphotransferase complex required for modification of newly synthesized lysosomal enzymes with the lysosomal targeting signal, mannose 6-phosphate. In the absence of S1P, the catalytically inactive α/ß-subunit precursor of GlcNAc-1-phosphotransferase fails to be activated and results in missorting of newly synthesized lysosomal enzymes, and lysosomal accumulation of non-degraded material, which are biochemical features of defective GlcNAc-1-phosphotransferase subunits and the associated pediatric lysosomal diseases mucolipidosis type II and III. The early embryonic death of S1P-deficient mice and the importance of various S1P-regulated biological processes, including lysosomal homeostasis, cautioned for clinical inhibition of S1P. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.


Assuntos
Colesterol/metabolismo , Mucolipidoses/genética , Pró-Proteína Convertases/genética , Proteólise , Serina Endopeptidases/genética , Animais , Colesterol/genética , Estresse do Retículo Endoplasmático/genética , Complexo de Golgi/metabolismo , Humanos , Lisossomos/genética , Camundongos , Mucolipidoses/patologia , Proteínas de Ligação a Elemento Regulador de Esterol/genética , Transferases (Outros Grupos de Fosfato Substituídos)/genética
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