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1.
Cell ; 184(24): 5950-5969.e22, 2021 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-34741801

RESUMO

The biogenesis of mammalian autophagosomes remains to be fully defined. Here, we used cellular and in vitro membrane fusion analyses to show that autophagosomes are formed from a hitherto unappreciated hybrid membrane compartment. The autophagic precursors emerge through fusion of FIP200 vesicles, derived from the cis-Golgi, with endosomally derived ATG16L1 membranes to generate a hybrid pre-autophagosomal structure, HyPAS. A previously unrecognized apparatus defined here controls HyPAS biogenesis and mammalian autophagosomal precursor membranes. HyPAS can be modulated by pharmacological agents whereas its formation is inhibited upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or by expression of SARS-CoV-2 nsp6. These findings reveal the origin of mammalian autophagosomal membranes, which emerge via convergence of secretory and endosomal pathways, and show that this process is targeted by microbial factors such as coronaviral membrane-modulating proteins.


Assuntos
Autofagossomos/virologia , COVID-19/virologia , Autofagia , COVID-19/metabolismo , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Retículo Endoplasmático/metabolismo , Endossomos/fisiologia , Endossomos/virologia , Complexo de Golgi/fisiologia , Células HEK293 , Células HeLa , Humanos , Fusão de Membrana , Microscopia Confocal , Fagossomos/metabolismo , Fagossomos/virologia , Proteínas Qa-SNARE/biossíntese , Receptores sigma/biossíntese , SARS-CoV-2 , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/biossíntese , Sinaptotagminas/biossíntese , Receptor Sigma-1
2.
Immunity ; 54(3): 437-453, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33691134

RESUMO

Autophagy is a quality-control, metabolic, and innate immunity process. Normative autophagy affects many cell types, including hematopoietic as well as non-hematopoietic, and promotes health in model organisms and humans. When autophagy is perturbed, this has repercussions on diseases with inflammatory components, including infections, autoimmunity and cancer, metabolic disorders, neurodegeneration, and cardiovascular and liver diseases. As a cytoplasmic degradative pathway, autophagy protects from exogenous hazards, including infection, and from endogenous sources of inflammation, including molecular aggregates and damaged organelles. The focus of this review is on the role of autophagy in inflammation, including type I interferon responses and inflammasome outputs, from molecules to immune cells. A special emphasis is given to the intersections of autophagy with innate immunity, immunometabolism, and functions of organelles such as mitochondria and lysosomes that act as innate immunity and immunometabolic signaling platforms.


Assuntos
Autofagia/imunologia , Sistema Imunitário/metabolismo , Infecções/imunologia , Inflamação/imunologia , Lisossomos/metabolismo , Animais , Autoimunidade , Humanos , Imunidade Inata , Transdução de Sinais
3.
Mol Cell ; 77(5): 951-969.e9, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-31995728

RESUMO

AMPK is a central regulator of metabolism and autophagy. Here we show how lysosomal damage activates AMPK. This occurs via a hitherto unrecognized signal transduction system whereby cytoplasmic sentinel lectins detect membrane damage leading to ubiquitination responses. Absence of Galectin 9 (Gal9) or loss of its capacity to recognize lumenal glycans exposed during lysosomal membrane damage abrogate such ubiquitination responses. Proteomic analyses with APEX2-Gal9 have revealed global changes within the Gal9 interactome during lysosomal damage. Gal9 association with lysosomal glycoproteins increases whereas interactions with a newly identified Gal9 partner, deubiquitinase USP9X, diminishes upon lysosomal injury. In response to damage, Gal9 displaces USP9X from complexes with TAK1 and promotes K63 ubiquitination of TAK1 thus activating AMPK on damaged lysosomes. This triggers autophagy and contributes to autophagic control of membrane-damaging microbe Mycobacterium tuberculosis. Thus, galectin and ubiquitin systems converge to activate AMPK and autophagy during endomembrane homeostasis.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia , Metabolismo Energético , Galectinas/metabolismo , Lisossomos/enzimologia , Ubiquitina/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Adolescente , Adulto , Animais , Autofagia/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Ativação Enzimática , Feminino , Galectinas/genética , Células HEK293 , Células HeLa , Humanos , Hipoglicemiantes/farmacologia , Lisossomos/efeitos dos fármacos , Lisossomos/microbiologia , Lisossomos/patologia , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Masculino , Metformina/farmacologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/patogenicidade , Transdução de Sinais , Células THP-1 , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Ubiquitinação , Adulto Jovem
4.
EMBO J ; 42(14): e112845, 2023 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-37272163

RESUMO

The canonical autophagy pathway in mammalian cells sequesters diverse cytoplasmic cargo within the double membrane autophagosomes that eventually convert into degradative compartments via fusion with endolysosomal intermediates. Here, we report that autophagosomal membranes show permeability in cells lacking principal ATG8 proteins (mATG8s) and are unable to mature into autolysosomes. Using a combination of methods including a novel in vitro assay to measure membrane sealing, we uncovered a previously unappreciated function of mATG8s to maintain autophagosomal membranes in a sealed state. The mATG8 proteins GABARAP and LC3A bind to key ESCRT-I components contributing, along with other ESCRTs, to the integrity and imperviousness of autophagic membranes. Autophagic organelles in cells lacking mATG8s are permeant, are arrested as amphisomes, and do not progress to functional autolysosomes. Thus, autophagosomal organelles need to be maintained in a sealed state in order to become lytic autolysosomes.


Assuntos
Autofagia , Proteínas Associadas aos Microtúbulos , Animais , Humanos , Família da Proteína 8 Relacionada à Autofagia/genética , Família da Proteína 8 Relacionada à Autofagia/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Autofagossomos/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Mamíferos
5.
Mol Cell ; 70(1): 120-135.e8, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29625033

RESUMO

The Ser/Thr protein kinase mTOR controls metabolic pathways, including the catabolic process of autophagy. Autophagy plays additional, catabolism-independent roles in homeostasis of cytoplasmic endomembranes and whole organelles. How signals from endomembrane damage are transmitted to mTOR to orchestrate autophagic responses is not known. Here we show that mTOR is inhibited by lysosomal damage. Lysosomal damage, recognized by galectins, leads to association of galectin-8 (Gal8) with the mTOR apparatus on the lysosome. Gal8 inhibits mTOR activity through its Ragulator-Rag signaling machinery, whereas galectin-9 activates AMPK in response to lysosomal injury. Both systems converge upon downstream effectors including autophagy and defense against Mycobacterium tuberculosis. Thus, a novel galectin-based signal-transduction system, termed here GALTOR, intersects with the known regulators of mTOR on the lysosome and controls them in response to lysosomal damage. VIDEO ABSTRACT.


Assuntos
Autofagia , Galectinas/metabolismo , Lisossomos/enzimologia , Serina-Treonina Quinases TOR/metabolismo , Tuberculose/enzimologia , Proteínas Quinases Ativadas por AMP/metabolismo , Sistemas de Transporte de Aminoácidos/genética , Sistemas de Transporte de Aminoácidos/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Galectinas/deficiência , Galectinas/genética , Células HEK293 , Células HeLa , Humanos , Lisossomos/microbiologia , Lisossomos/patologia , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Complexos Multiproteicos , Mycobacterium tuberculosis/patogenicidade , Transdução de Sinais , Células THP-1 , Serina-Treonina Quinases TOR/genética , Tuberculose/genética , Tuberculose/microbiologia , Tuberculose/patologia
6.
EMBO J ; 40(19): e108863, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34459017

RESUMO

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.


Assuntos
Autofagia , Suscetibilidade a Doenças , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Autofagia/imunologia , Biomarcadores , Regulação da Expressão Gênica , Predisposição Genética para Doença , Homeostase , Interações Hospedeiro-Patógeno , Humanos , Especificidade de Órgãos , Transdução de Sinais
7.
EMBO J ; 38(22): e101994, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31625181

RESUMO

Mammalian homologs of yeast Atg8 protein (mAtg8s) are important in autophagy, but their exact mode of action remains ill-defined. Syntaxin 17 (Stx17), a SNARE with major roles in autophagy, was recently shown to bind mAtg8s. Here, we identified LC3-interacting regions (LIRs) in several SNAREs that broaden the landscape of the mAtg8-SNARE interactions. We found that Syntaxin 16 (Stx16) and its cognate SNARE partners all have LIR motifs and bind mAtg8s. Knockout of Stx16 caused defects in lysosome biogenesis, whereas a Stx16 and Stx17 double knockout completely blocked autophagic flux and decreased mitophagy, pexophagy, xenophagy, and ribophagy. Mechanistic analyses revealed that mAtg8s and Stx16 control several properties of lysosomal compartments including their function as platforms for active mTOR. These findings reveal a broad direct interaction of mAtg8s with SNAREs with impact on membrane remodeling in eukaryotic cells and expand the roles of mAtg8s to lysosome biogenesis.


Assuntos
Autofagossomos/metabolismo , Família da Proteína 8 Relacionada à Autofagia/metabolismo , Autofagia , Lisossomos/metabolismo , Proteínas Qa-SNARE/metabolismo , Sintaxina 16/metabolismo , Motivos de Aminoácidos , Família da Proteína 8 Relacionada à Autofagia/genética , Células HEK293 , Células HeLa , Humanos , Redes e Vias Metabólicas , Ligação Proteica , Domínios Proteicos , Proteínas Qa-SNARE/antagonistas & inibidores , Proteínas Qa-SNARE/genética , RNA Interferente Pequeno/genética , Sintaxina 16/antagonistas & inibidores , Sintaxina 16/genética
8.
Mol Cell ; 58(3): 507-21, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25891078

RESUMO

IRGM, encoded by a uniquely human gene conferring risk for inflammatory diseases, affects autophagy through an unknown mechanism. Here, we show how IRGM controls autophagy. IRGM interacts with ULK1 and Beclin 1 and promotes their co-assembly thus governing the formation of autophagy initiation complexes. We further show that IRGM interacts with pattern recognition receptors including NOD2. IRGM, NOD2, and ATG16L1, all of which are Crohn's disease risk factors, form a molecular complex to modulate autophagic responses to microbial products. NOD2 enhances K63-linked polyubiquitination of IRGM, which is required for interactions of IRGM with the core autophagy factors and for microbial clearance. Thus, IRGM plays a direct role in organizing the core autophagy machinery to endow it with antimicrobial and anti-inflammatory functions.


Assuntos
Anti-Infecciosos/metabolismo , Autofagia , Doença de Crohn/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteína Homóloga à Proteína-1 Relacionada à Autofagia , Proteínas Relacionadas à Autofagia , Proteína Beclina-1 , Western Blotting , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Doença de Crohn/genética , Proteínas de Ligação ao GTP/genética , Expressão Gênica , Células HCT116 , Células HEK293 , Células HT29 , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Microscopia Confocal , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , Ligação Proteica , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , Receptores de Reconhecimento de Padrão/genética , Receptores de Reconhecimento de Padrão/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células U937 , Ubiquitinação
9.
EMBO J ; 36(1): 42-60, 2017 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-27932448

RESUMO

Autophagy is a process delivering cytoplasmic components to lysosomes for degradation. Autophagy may, however, play a role in unconventional secretion of leaderless cytosolic proteins. How secretory autophagy diverges from degradative autophagy remains unclear. Here we show that in response to lysosomal damage, the prototypical cytosolic secretory autophagy cargo IL-1ß is recognized by specialized secretory autophagy cargo receptor TRIM16 and that this receptor interacts with the R-SNARE Sec22b to recruit cargo to the LC3-II+ sequestration membranes. Cargo secretion is unaffected by downregulation of syntaxin 17, a SNARE promoting autophagosome-lysosome fusion and cargo degradation. Instead, Sec22b in combination with plasma membrane syntaxin 3 and syntaxin 4 as well as SNAP-23 and SNAP-29 completes cargo secretion. Thus, secretory autophagy utilizes a specialized cytosolic cargo receptor and a dedicated SNARE system. Other unconventionally secreted cargo, such as ferritin, is secreted via the same pathway.


Assuntos
Autofagia , Proteínas de Ligação a DNA/metabolismo , Interleucina-1beta/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas R-SNARE/metabolismo , Fatores de Transcrição/metabolismo , Linhagem Celular , Ferritinas/metabolismo , Humanos , Monócitos/metabolismo , Proteínas Qa-SNARE/metabolismo , Proteínas Qb-SNARE/metabolismo , Proteínas Qc-SNARE/metabolismo , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases
10.
EMBO J ; 36(13): 1811-1836, 2017 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-28596378

RESUMO

Over the past two decades, the molecular machinery that underlies autophagic responses has been characterized with ever increasing precision in multiple model organisms. Moreover, it has become clear that autophagy and autophagy-related processes have profound implications for human pathophysiology. However, considerable confusion persists about the use of appropriate terms to indicate specific types of autophagy and some components of the autophagy machinery, which may have detrimental effects on the expansion of the field. Driven by the overt recognition of such a potential obstacle, a panel of leading experts in the field attempts here to define several autophagy-related terms based on specific biochemical features. The ultimate objective of this collaborative exchange is to formulate recommendations that facilitate the dissemination of knowledge within and outside the field of autophagy research.


Assuntos
Autofagia , Terminologia como Assunto , Animais , Caenorhabditis elegans/fisiologia , Drosophila melanogaster/fisiologia , Redes Reguladoras de Genes , Camundongos , Saccharomyces cerevisiae/fisiologia
11.
J Cell Sci ; 132(23)2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31685529

RESUMO

The tripartite motif (TRIM) proteins constitute a family of ubiquitin E3 ligases involved in a multitude of cellular processes, including protein homeostasis and autophagy. TRIM32 is characterized by six protein-protein interaction domains termed NHL, various point mutations in which are associated with limb-girdle-muscular dystrophy 2H (LGMD2H). Here, we show that TRIM32 is an autophagy substrate. Lysosomal degradation of TRIM32 was dependent on ATG7 and blocked by knockout of the five autophagy receptors p62 (also known as SQSTM1), NBR1, NDP52 (also known as CALCOCO2), TAX1BP1 and OPTN, pointing towards degradation by selective autophagy. p62 directed TRIM32 to lysosomal degradation, while TRIM32 mono-ubiquitylated p62 on lysine residues involved in regulation of p62 activity. Loss of TRIM32 impaired p62 sequestration, while reintroduction of TRIM32 facilitated p62 dot formation and its autophagic degradation. A TRIM32LGMD2H disease mutant was unable to undergo autophagic degradation and to mono-ubiquitylate p62, and its reintroduction into the TRIM32-knockout cells did not affect p62 dot formation. In light of the important roles of autophagy and p62 in muscle cell proteostasis, our results point towards impaired TRIM32-mediated regulation of p62 activity as a pathological mechanisms in LGMD2H.


Assuntos
Distrofias Musculares/metabolismo , Proteína Sequestossoma-1/metabolismo , Fatores de Transcrição/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Autofagia/genética , Autofagia/fisiologia , Células HEK293 , Células HeLa , Humanos , Imunoprecipitação , Distrofias Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Ligação Proteica , Proteína Sequestossoma-1/genética , Fatores de Transcrição/genética , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética
12.
Immunity ; 37(2): 223-34, 2012 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-22921120

RESUMO

Autophagy is a fundamental biological process of the eukaryotic cell contributing to diverse cellular and physiological functions including cell-autonomous defense against intracellular pathogens. Here, we screened the Rab family of membrane trafficking regulators for effects on autophagic elimination of Mycobacterium tuberculosis var. bovis BCG and found that Rab8b and its downstream interacting partner, innate immunity regulator TBK-1, are required for autophagic elimination of mycobacteria in macrophages. TBK-1 was necessary for autophagic maturation. TBK-1 coordinated assembly and function of the autophagic machinery and phosphorylated the autophagic adaptor p62 (sequestosome 1) on Ser-403, a residue essential for its role in autophagic clearance. A key proinflammatory cytokine, IL-1ß, induced autophagy leading to autophagic killing of mycobacteria in macrophages, and this IL-1ß activity was dependent on TBK-1. Thus, TBK-1 is a key regulator of immunological autophagy and is responsible for the maturation of autophagosomes into lytic bactericidal organelles.


Assuntos
Autofagia/imunologia , Macrófagos/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Proteínas rab de Ligação ao GTP/imunologia , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteína 7 Relacionada à Autofagia , Proteínas de Fluorescência Verde , Células HeLa , Proteínas de Choque Térmico/imunologia , Proteínas de Choque Térmico/metabolismo , Humanos , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Microscopia Confocal , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/genética , Mycobacterium bovis/imunologia , Fagossomos/efeitos dos fármacos , Fagossomos/imunologia , Fagossomos/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , RNA Interferente Pequeno , Proteína Sequestossoma-1 , Serina/imunologia , Serina/metabolismo , Tuberculose/imunologia , Proteínas rab de Ligação ao GTP/genética
13.
Semin Cell Dev Biol ; 83: 36-41, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29580970

RESUMO

The autophagy pathway known also as macroautophagy (herein referred to as autophagy) is characterized by the formation of double-membrane organelles that capture cytosolic material. Based on pathway termination alternatives, autophagy has been divided into degradative and secretory. During degradative autophagy, autophagosomes typically fuse with lysosomes upon which the sequestered material is degraded. During secretory autophagy, instead of degradation the sequestered cargo is subjected to active secretion or passive release. In this review, we focus on the mechanisms of secretion/passive release of the potent pro-inflammatory cytokine IL-1ß, as a prototypical leaderless cytosolic protein cargo studied in the context of secretory autophagy.


Assuntos
Autofagia/fisiologia , Interleucina-1beta/metabolismo , Humanos
14.
Immunity ; 32(3): 329-41, 2010 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-20206555

RESUMO

Autophagy allows cells to self-digest portions of their own cytoplasm for a multitude of physiological purposes, including innate and adaptive immunity functions. In one of its innate immunity manifestations, autophagy, is known to contribute to the killing of intracellular microbes, including Mycobacterium tuberculosis, although the molecular mechanisms have been unclear. Here, we delineated sequential steps of the autophagic pathway necessary to control intracellular M. tuberculosis and found that in addition to autophagy initiation and maturation, an accessory autophagy-targeting molecule p62 (A170 or SQSTM1) was required for mycobactericidal activity. The p62 adaptor protein delivered specific ribosomal and bulk ubiquitinated cytosolic proteins to autolysosomes where they were proteolytically converted into products capable of killing M. tuberculosis. Thus, p62 brings cytosolic proteins to autolysosomes where they are processed from innocuous precursors into neo-antimicrobial peptides, explaining in part the unique bactericidal properties of autophagic organelles.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Autofagia , Citosol/imunologia , Proteínas de Choque Térmico/imunologia , Mycobacterium tuberculosis/imunologia , Animais , Transporte Biológico , Células Cultivadas , Citosol/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fagossomos/imunologia , Fagossomos/metabolismo , Ligação Proteica , Proteína Sequestossoma-1 , Ubiquitina/metabolismo
15.
Immunity ; 32(5): 654-69, 2010 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-20451412

RESUMO

Dendritic cells (DCs) in mucosal surfaces are early targets for human immunodeficiency virus-1 (HIV-1). DCs mount rapid and robust immune responses upon pathogen encounter. However, immune response in the early events of HIV-1 transmission appears limited, suggesting that HIV-1 evade early immune control by DCs. We report that HIV-1 induces a rapid shutdown of autophagy and immunoamphisomes in DCs. HIV-1 envelope activated the mammalian target of rapamycin pathway in DCs, leading to autophagy exhaustion. HIV-1-induced inhibition of autophagy in DC increased cell-associated HIV-1 and transfer of HIV-1 infection to CD4(+) T cells. HIV-1-mediated downregulation of autophagy in DCs impaired innate and adaptive immune responses. Immunoamphisomes in DCs engulf incoming pathogens and appear to amplify pathogen degradation as well as Toll-like receptor responses and antigen presentation. The findings that HIV-1 downregulates autophagy and impedes immune functions of DCs represent a pathogenesis mechanism that can be pharmacologically countered with therapeutic and prophylactic implications.


Assuntos
Imunidade Adaptativa , Células Dendríticas/imunologia , Células Dendríticas/virologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Imunidade Inata , Fagossomos/imunologia , Autofagia , Sequência de Bases , Linfócitos T CD4-Positivos/virologia , Células Cultivadas , Células Dendríticas/patologia , Regulação para Baixo , Citometria de Fluxo , Humanos , Immunoblotting , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lisossomos/imunologia , Lisossomos/virologia , Dados de Sequência Molecular , Fagossomos/virologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR
16.
Artigo em Inglês | MEDLINE | ID: mdl-30012752

RESUMO

Host-directed therapy in tuberculosis is a potential adjunct to antibiotic chemotherapy directed at Mycobacterium tuberculosis Ambroxol, a lead compound, emerged from a screen for autophagy-inducing drugs. At clinically relevant doses, ambroxol induced autophagy in vitro and in vivo and promoted mycobacterial killing in macrophages. Ambroxol also potentiated rifampin activity in a murine tuberculosis model.


Assuntos
Ambroxol/farmacologia , Antituberculosos/farmacologia , Autofagia/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Rifampina/farmacologia , Tuberculose/tratamento farmacológico , Animais , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Tuberculose/microbiologia
17.
J Cell Sci ; 129(5): 881-91, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26906420

RESUMO

Selective autophagy entails cooperation between target recognition and assembly of the autophagic apparatus. Target recognition is conducted by receptors that often recognize tags, such as ubiquitin and galectins, although examples of selective autophagy independent of these tags are emerging. It is less known how receptors cooperate with the upstream autophagic regulators, beyond the well-characterized association of receptors with Atg8 or its homologs, such as LC3B (encoded by MAP1LC3B), on autophagic membranes. The molecular details of the emerging role in autophagy of the family of proteins called TRIMs shed light on the coordination between cargo recognition and the assembly and activation of the principal autophagy regulators. In their autophagy roles, TRIMs act both as receptors and as platforms ('receptor regulators') for the assembly of the core autophagy regulators, such as ULK1 and Beclin 1 in their activated state. As autophagic receptors, TRIMs can directly recognize endogenous or exogenous targets, obviating a need for intermediary autophagic tags, such as ubiquitin and galectins. The receptor and regulatory features embodied within the same entity allow TRIMs to govern cargo degradation in a highly exact process termed 'precision autophagy'.


Assuntos
Autofagia , Proteínas com Motivo Tripartido/fisiologia , Animais , Humanos , Transdução de Sinais
18.
J Cell Sci ; 129(19): 3562-3573, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27562068

RESUMO

TRIM proteins contribute to selective autophagy, a process whereby cells target specific cargo for autophagic degradation. In a previously reported screen, TRIM17 acted as a prominent inhibitor of bulk autophagy, unlike the majority of TRIMs, which had positive roles. Nevertheless, TRIM17 showed biochemical hallmarks of autophagy-inducing TRIMs. To explain this paradox, here, we investigated how TRIM17 inhibits selective autophagic degradation of a subset of targets while promoting degradation of others. We traced the inhibitory function of TRIM17 to its actions on the anti-autophagy protein Mcl-1, which associates with and inactivates Beclin 1. TRIM17 expression stabilized Mcl-1-Beclin-1 complexes. Despite its ability to inhibit certain types of selective autophagy, TRIM17 promoted the removal of midbodies, remnants of the cell division machinery that are known autophagy targets. The selective loss of anti-autophagy Mcl-1 from TRIM17-Beclin-1 complexes at midbodies correlated with the ability of TRIM17 to promote midbody removal. This study further expands the roles of TRIMs in regulating selective autophagy by showing that a single TRIM can, depending upon a target, either positively or negatively regulate autophagy.


Assuntos
Autofagia , Proteínas de Transporte/metabolismo , Núcleo Celular/metabolismo , Proteína Beclina-1/metabolismo , Capsídeo/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células HEK293 , HIV-1/metabolismo , Células HeLa , Humanos , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , RNA Interferente Pequeno/metabolismo , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases
19.
Immunity ; 30(4): 479-81, 2009 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-19371713

RESUMO

Autophagy has many roles in immunity, including the control of intracellular microbes by a cell-autonomous mechanism. In this issue of Immunity, Shelly et al. (2009) use VSV infection in Drosophila to show the role of autophagy genes in controlling viruses.


Assuntos
Autofagia/imunologia , Imunidade , Viroses/imunologia , Animais , Humanos
20.
EMBO J ; 30(23): 4701-11, 2011 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-22068051

RESUMO

Autophagy controls the quality and quantity of the eukaryotic cytoplasm while performing two evolutionarily highly conserved functions: cell-autonomous provision of energy and nutrients by cytosol autodigestion during starvation, and removal of defunct organelles and large aggregates exceeding the capacity of other cellular degradative systems. In contrast to these autodigestive processes, autophagy in yeast has additional, biogenesis functions. However, no equivalent biosynthetic roles have been described for autophagy in mammals. Here, we show that in mammalian cells, autophagy has a hitherto unappreciated positive contribution to the biogenesis and secretion of the proinflammatory cytokine IL-1ß via an export pathway that depends on Atg5, inflammasome, at least one of the two mammalian Golgi reassembly stacking protein (GRASP) paralogues, GRASP55 (GORASP2) and Rab8a. This process, which is a type of unconventional secretion, expands the functional manifestations of autophagy beyond autodigestive and quality control roles in mammals. It enables a subset of cytosolic proteins devoid of signal peptide sequences, and thus unable to access the conventional pathway through the ER, to enter an autophagy-based secretory pathway facilitating their exit from the cytoplasm.


Assuntos
Autofagia/fisiologia , Proteínas de Transporte/metabolismo , Interleucina-1beta , Proteínas de Membrana/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Animais , Autofagia/efeitos dos fármacos , Proteína 5 Relacionada à Autofagia , Células Cultivadas , Proteína HMGB1/metabolismo , Inflamassomos/metabolismo , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas Luminescentes/metabolismo , Macrolídeos/farmacologia , Macrófagos/metabolismo , Camundongos , Nigericina/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Via Secretória/efeitos dos fármacos , Via Secretória/fisiologia
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