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1.
Dev Cell ; 59(11): 1410-1424.e4, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38593803

RESUMO

Endoplasmic reticulum exit sites (ERESs) are tubular outgrowths of endoplasmic reticulum that serve as the earliest station for protein sorting and export into the secretory pathway. How these structures respond to different cellular conditions remains unclear. Here, we report that ERESs undergo lysosome-dependent microautophagy when Ca2+ is released by lysosomes in response to nutrient stressors such as mTOR inhibition or amino acid starvation in mammalian cells. Targeting and uptake of ERESs into lysosomes were observed by super-resolution live-cell imaging and focus ion beam scanning electron microscopy (FIB-SEM). The mechanism was ESCRT dependent and required ubiquitinated SEC31, ALG2, and ALIX, with a knockout of ALG2 or function-blocking mutations of ALIX preventing engulfment of ERESs by lysosomes. In vitro, reconstitution of the pathway was possible using lysosomal lipid-mimicking giant unilamellar vesicles and purified recombinant components. Together, these findings demonstrate a pathway of lysosome-dependent ERES microautophagy mediated by COPII, ALG2, and ESCRTS induced by nutrient stress.


Assuntos
Vesículas Revestidas pelo Complexo de Proteína do Envoltório , Proteínas de Ligação ao Cálcio , Retículo Endoplasmático , Complexos Endossomais de Distribuição Requeridos para Transporte , Lisossomos , Microautofagia , Proteínas de Transporte Vesicular , Lisossomos/metabolismo , Retículo Endoplasmático/metabolismo , Humanos , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genética , Vesículas Revestidas pelo Complexo de Proteína do Envoltório/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Proteínas de Transporte Vesicular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Transporte Proteico , Células HeLa , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/genética , Autofagia/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Cálcio/metabolismo
2.
Mol Biol Cell ; 35(5): ar70, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38536415

RESUMO

Lysosome turnover and biogenesis are induced in response to treatment of cells with agents that cause membrane rupture, but whether other stress conditions engage similar homeostatic mechanisms is not well understood. Recently we described a form of selective turnover of lysosomes that is induced by metabolic stress or by treatment of cells with ionophores or lysosomotropic agents, involving the formation of intraluminal vesicles within intact organelles through microautophagy. Selective turnover involves noncanonical autophagy and the lipidation of LC3 onto lysosomal membranes, as well as the autophagy gene-dependent formation of intraluminal vesicles. Here, we find a form of microautophagy induction that requires activity of the lipid kinase PIKfyve and is associated with the nuclear translocation of TFEB, a known mediator of lysosome biogenesis. We show that LC3 undergoes turnover during this process, and that PIKfyve is required for the formation of intraluminal vesicles and LC3 turnover, but not for LC3 lipidation onto lysosomal membranes, demonstrating that microautophagy is regulated by PIKfyve downstream of noncanonical autophagy. We further show that TFEB activation requires noncanonical autophagy but not PIKfyve, distinguishing the regulation of biogenesis from microautophagy occurring in response to agents that induce lysosomal stress.


Assuntos
Lisossomos , Microautofagia , Autofagia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Membranas Intracelulares/metabolismo , Ionóforos , Lisossomos/metabolismo , Humanos , Linhagem Celular Tumoral
3.
J Nippon Med Sch ; 91(1): 2-9, 2024 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-37271546

RESUMO

Autophagy is a self-digestive process that is conserved in eukaryotic cells and responsible for maintaining cellular homeostasis through proteolysis. By this process, cells break down their own components in lysosomes. Autophagy can be classified into three categories: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Macroautophagy involves membrane elongation and microautophagy involves membrane internalization, and both pathways undergo selective or non-selective processes that transport cytoplasmic components into lysosomes to be degraded. CMA, however, involves selective incorporation of cytosolic materials into lysosomes without membrane deformation. All three categories of autophagy have attracted much attention due to their involvement in various biological phenomena and their relevance to human diseases, such as neurodegenerative diseases and cancer. Clarification of the molecular mechanisms behind these processes is key to understanding autophagy and recent studies have made major progress in this regard, especially for the mechanisms of initiation and membrane elongation in macroautophagy and substrate recognition in microautophagy and CMA. Furthermore, it is becoming evident that the three categories of autophagy are related to each other despite their implementation by different sets of proteins and the involvement of completely different membrane dynamics. In this review, recent progress in macroautophagy, microautophagy, and CMA are summarized.


Assuntos
Autofagia Mediada por Chaperonas , Doenças Neurodegenerativas , Humanos , Microautofagia , Macroautofagia , Autofagia , Doenças Neurodegenerativas/metabolismo
4.
FEBS Lett ; 598(1): 48-58, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37857501

RESUMO

The discovery of microautophagy, the direct engulfment of cytoplasmic material by the lysosome, dates back to 1966 in a morphological study of mammalian cells by Christian de Duve. Since then, studies on microautophagy have shifted toward the elucidation of the physiological significance of the process. However, in contrast to macroautophagy, studies on the molecular mechanisms of microautophagy have been limited. Only recent studies revealed that ATG proteins involved in macroautophagy are also operative in several types of microautophagy and that ESCRT proteins, responsible for the multivesicular body pathway, play a central role in most microautophagy processes. In this review, we summarize our current knowledge on the function of ATG and ESCRT proteins in microautophagy.


Assuntos
Autofagia , Microautofagia , Animais , Autofagia/fisiologia , Lisossomos/metabolismo , Citosol/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Mamíferos/metabolismo
5.
Trends Cell Biol ; 34(7): 606-616, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38104013

RESUMO

Autophagy is a self-catabolic process through which cellular components are delivered to lysosomes for degradation. There are three types of autophagy, i.e., macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. In macroautophagy, a portion of the cytoplasm is wrapped by the autophagosome, which then fuses with lysosomes and delivers the engulfed cytoplasm for degradation. In CMA, the translocation of cytosolic substrates to the lysosomal lumen is directly across the limiting membrane of lysosomes. In microautophagy, lytic organelles, including endosomes or lysosomes, take up a portion of the cytoplasm directly. Although macroautophagy has been investigated extensively, microautophagy has received much less attention. Nonetheless, it has become evident that microautophagy plays a variety of cellular roles from yeast to mammals. Here we review the very recent updates of microautophagy. In particular, we focus on the feature of the degradative substrates and the molecular machinery that mediates microautophagy.


Assuntos
Lisossomos , Microautofagia , Lisossomos/metabolismo , Animais , Humanos , Mamíferos/metabolismo , Autofagia , Autofagossomos/metabolismo
6.
Cell Rep ; 42(12): 113529, 2023 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-38060380

RESUMO

Chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI) are pathways for selective degradation of cytosolic proteins in lysosomes and late endosomes, respectively. These autophagic processes share as a first step the recognition of the same five-amino-acid motif in substrate proteins by the Hsc70 chaperone, raising the possibility of coordinated activity of both pathways. In this work, we show the existence of a compensatory relationship between CMA and eMI and identify a role for the chaperone protein Bag6 in triage and internalization of eMI substrates into late endosomes. Association and dynamics of Bag6 at the late endosome membrane change during starvation, a stressor that, contrary to other autophagic pathways, causes a decline in eMI activity. Collectively, these results show a coordinated function of eMI with CMA, identify the interchangeable subproteome degraded by these pathways, and start to elucidate the molecular mechanisms that facilitate the switch between them.


Assuntos
Autofagia Mediada por Chaperonas , Microautofagia , Autofagia , Endossomos/metabolismo , Lisossomos/metabolismo , Chaperonas Moleculares/metabolismo
7.
EMBO Rep ; 24(12): e57300, 2023 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-37987447

RESUMO

Lysosomes are degradative organelles and signaling hubs that maintain cell and tissue homeostasis, and lysosomal dysfunction is implicated in aging and reduced longevity. Lysosomes are frequently damaged, but their repair mechanisms remain unclear. Here, we demonstrate that damaged lysosomal membranes are repaired by microautophagy (a process termed "microlysophagy") and identify key regulators of the first and last steps. We reveal the AGC kinase STK38 as a novel microlysophagy regulator. Through phosphorylation of the scaffold protein DOK1, STK38 is specifically required for the lysosomal recruitment of the AAA+ ATPase VPS4, which terminates microlysophagy by promoting the disassembly of ESCRT components. By contrast, microlysophagy initiation involves non-canonical lipidation of ATG8s, especially the GABARAP subfamily, which is required for ESCRT assembly through interaction with ALIX. Depletion of STK38 and GABARAPs accelerates DNA damage-induced cellular senescence in human cells and curtails lifespan in C. elegans, respectively. Thus, microlysophagy is regulated by STK38 and GABARAPs and could be essential for maintaining lysosomal integrity and preventing aging.


Assuntos
Caenorhabditis elegans , Microautofagia , Animais , Humanos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Lisossomos/metabolismo , Membranas Intracelulares/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Autofagia , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo
8.
Int J Mol Sci ; 24(18)2023 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-37762105

RESUMO

The heat shock factor 1 (HSF1)-mediated stress response pathway and autophagy processes play important roles in the maintenance of proteostasis. Autophagy processes are subdivided into three subtypes: macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. Recently, molecular chaperones and co-factors were shown to be involved in the selective degradation of substrates by these three autophagy processes. This evidence suggests that autophagy processes are regulated in a coordinated manner by the HSF1-mediated stress response pathway. Recently, various studies have demonstrated that proteostasis pathways including HSF1 and autophagy are implicated in longevity. Furthermore, they serve as therapeutic targets for aging-related diseases such as cancer and neurodegenerative diseases. In the future, these studies will underpin the development of therapies against various diseases.


Assuntos
Autofagia , Autofagia Mediada por Chaperonas , Macroautofagia , Microautofagia , Longevidade
9.
Plant Physiol ; 193(4): 2361-2380, 2023 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-37619984

RESUMO

Lipid droplets (LDs) of seed tissues are storage organelles for triacylglycerols (TAGs) that provide the energy and carbon for seedling establishment. In the major route of LD degradation (lipolysis), TAGs are mobilized by lipases. However, LDs may also be degraded via lipophagy, a type of selective autophagy, which mediates LD delivery to vacuoles or lysosomes. The exact mechanisms of LD degradation and the mobilization of their content in plants remain unresolved. Here, we provide evidence that LDs are degraded via a process morphologically resembling microlipophagy in Arabidopsis (Arabidopsis thaliana) seedlings. We observed the entry and presence of LDs in the central vacuole as well as their breakdown. Moreover, we show co-localization of AUTOPHAGY-RELATED PROTEIN 8b (ATG8b) and LDs during seed germination and localization of lipidated ATG8 (ATG8-PE) to the LD fraction. We further demonstrate that structural LD proteins from the caleosin family, CALEOSIN 1 (CLO1), CALEOSIN 2 (CLO2), and CALEOSIN 3 (CLO3), interact with ATG8 proteins and possess putative ATG8-interacting motifs (AIMs). Deletion of the AIM localized directly before the proline knot disrupts the interaction of CLO1 with ATG8b, suggesting a possible role of this region in the interaction between these proteins. Collectively, we provide insights into LD degradation by microlipophagy in germinating seeds with a particular focus on the role of structural LD proteins in this process.


Assuntos
Arabidopsis , Plântula , Arabidopsis/genética , Arabidopsis/metabolismo , Autofagia , Proteínas Relacionadas à Autofagia/metabolismo , Gotículas Lipídicas/metabolismo , Microautofagia , Plântula/genética , Plântula/metabolismo , Triglicerídeos/metabolismo
11.
Cells ; 12(9)2023 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-37174722

RESUMO

Physiologically, autophagy is an evolutionarily conserved and self-degradative process in cells. Autophagy carries out normal physiological roles throughout mammalian life. Accumulating evidence shows autophagy as a mechanism for cellular growth, development, differentiation, survival, and homeostasis. In male reproductive systems, normal spermatogenesis and steroidogenesis need a balance between degradation and energy supply to preserve cellular metabolic homeostasis. The main process of autophagy includes the formation and maturation of the phagophore, autophagosome, and autolysosome. Autophagy is controlled by a group of autophagy-related genes that form the core machinery of autophagy. Three types of autophagy mechanisms have been discovered in mammalian cells: macroautophagy, microautophagy, and chaperone-mediated autophagy. Autophagy is classified as non-selective or selective. Non-selective macroautophagy randomly engulfs the cytoplasmic components in autophagosomes that are degraded by lysosomal enzymes. While selective macroautophagy precisely identifies and degrades a specific element, current findings have shown the novel functional roles of autophagy in male reproduction. It has been recognized that dysfunction in the autophagy process can be associated with male infertility. Overall, this review provides an overview of the cellular and molecular basics of autophagy and summarizes the latest findings on the key role of autophagy in mammalian male reproductive physiology.


Assuntos
Autofagia , Macroautofagia , Animais , Masculino , Autofagossomos/metabolismo , Microautofagia , Lisossomos/metabolismo , Mamíferos
13.
Nat Cell Biol ; 25(3): 453-466, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36918692

RESUMO

Stimulator of interferon genes (STING) is essential for the type I interferon response against a variety of DNA pathogens. Upon emergence of cytosolic DNA, STING translocates from the endoplasmic reticulum to the Golgi where STING activates the downstream kinase TBK1, then to lysosome through recycling endosomes (REs) for its degradation. Although the molecular machinery of STING activation is extensively studied and defined, the one underlying STING degradation and inactivation has not yet been fully elucidated. Here we show that STING is degraded by the endosomal sorting complexes required for transport (ESCRT)-driven microautophagy. Airyscan super-resolution microscopy and correlative light/electron microscopy suggest that STING-positive vesicles of an RE origin are directly encapsulated into Lamp1-positive compartments. Screening of mammalian Vps genes, the yeast homologues of which regulate Golgi-to-vacuole transport, shows that ESCRT proteins are essential for the STING encapsulation into Lamp1-positive compartments. Knockdown of Tsg101 and Vps4, components of ESCRT, results in the accumulation of STING vesicles in the cytosol, leading to the sustained type I interferon response. Knockdown of Tsg101 in human primary T cells leads to an increase the expression of interferon-stimulated genes. STING undergoes K63-linked ubiquitination at lysine 288 during its transit through the Golgi/REs, and this ubiquitination is required for STING degradation. Our results reveal a molecular mechanism that prevents hyperactivation of innate immune signalling, which operates at REs.


Assuntos
Complexos Endossomais de Distribuição Requeridos para Transporte , Interferon Tipo I , Proteínas de Membrana , Animais , Humanos , Adenosina Trifosfatases/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Endossomos/metabolismo , Microautofagia , Transporte Proteico , Transdução de Sinais , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo
14.
Nat Rev Mol Cell Biol ; 24(3): 186-203, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36097284

RESUMO

'Autophagy' refers to an evolutionarily conserved process through which cellular contents, such as damaged organelles and protein aggregates, are delivered to lysosomes for degradation. Different forms of autophagy have been described on the basis of the nature of the cargoes and the means used to deliver them to lysosomes. At present, the prevailing categories of autophagy in mammalian cells are macroautophagy, microautophagy and chaperone-mediated autophagy. The molecular mechanisms and biological functions of macroautophagy and chaperone-mediated autophagy have been extensively studied, but microautophagy has received much less attention. In recent years, there has been a growth in research on microautophagy, first in yeast and then in mammalian cells. Here we review this form of autophagy, focusing on selective forms of microautophagy. We also discuss the upstream regulatory mechanisms, the crosstalk between macroautophagy and microautophagy, and the functional implications of microautophagy in diseases such as cancer and neurodegenerative disorders in humans. Future research into microautophagy will provide opportunities to develop novel interventional strategies for autophagy- and lysosome-related diseases.


Assuntos
Autofagia , Microautofagia , Animais , Humanos , Lisossomos/metabolismo , Comunicação Celular , Macroautofagia , Mamíferos
15.
Aging Cell ; 21(10): e13713, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36116133

RESUMO

Autophagy is essential for protein quality control and regulation of the functional proteome. Failure of autophagy pathways with age contributes to loss of proteostasis in aged organisms and accelerates the progression of age-related diseases. In this work, we show that activity of endosomal microautophagy (eMI), a selective type of autophagy occurring in late endosomes, declines with age and identify the sub-proteome affected by this loss of function. Proteomics of late endosomes from old mice revealed an aberrant glycation signature for Hsc70, the chaperone responsible for substrate targeting to eMI. Age-related Hsc70 glycation reduces its stability in late endosomes by favoring its organization into high molecular weight protein complexes and promoting its internalization/degradation inside late endosomes. Reduction of eMI with age associates with an increase in protein secretion, as late endosomes can release protein-loaded exosomes upon plasma membrane fusion. Our search for molecular mediators of the eMI/secretion switch identified the exocyst-RalA complex, known for its role in exocytosis, as a novel physiological eMI inhibitor that interacts with Hsc70 and acts directly at the late endosome membrane. This inhibitory function along with the higher exocyst-RalA complex levels detected in late endosomes from old mice could explain, at least in part, reduced eMI activity with age. Interaction of Hsc70 with components of the exocyst-RalA complex places this chaperone in the switch from eMI to secretion. Reduced intracellular degradation in favor of extracellular release of undegraded material with age may be relevant to the spreading of proteotoxicity associated with aging and progression of proteinopathies.


Assuntos
Microautofagia , Proteoma , Envelhecimento , Animais , Autofagia/fisiologia , Endossomos/metabolismo , Lisossomos/metabolismo , Camundongos , Transporte Proteico , Proteoma/metabolismo
16.
Antiviral Res ; 207: 105417, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36122619

RESUMO

Naturally evolved immune-escape PreS2 mutant is an oncogenic caveat of liver cirrhosis and hepatocellular carcinoma (HCC) during chronic hepatitis B virus (HBV) infection. PreS2 mutant is prevalent in above 50% of patients with HCC. In addition, intrahepatic expression of PreS2 mutant large surface antigen (PreS2-LHBS) induces endoplasmic reticulum stress, mitochondria dysfunction, cytokinesis failure, and subsequent chromosome hyperploidy. As PreS2-LHBS has no enzymatic activity, the development of PreS2-specific inhibitors can be challenging. In this study, we aim to identify inhibitors of PreS2-LHBS via the induction of protein-specific degradation. We set up a large-scale protein stability reporter platform and applied an FDA-approved drug library for the screening. We identified ABT199 as a negative modulator of PreS2-LHBS, which induced the degradation of PreS2-LHBS without affecting the general cell viability in both hepatoma and immortalized hepatocytes. Next, by affinity purification screening, we found that PreS2-LHBS interacted with HSC70, a microautophagy mediating chaperone. Simultaneously, inhibitions of lysosomal degradation or microautophagy restored the expression of PreS2-LHBS, suggesting microautophagy is involved in ABT199-induced PreS2-LHBS degradation. Notably, a 24-hr treatment of ABT199 was sufficient for the reduction of DNA damage and cytokinesis failure in PreS2-LHBS expressing hepatocytes. In addition, a persistent treatment of ABT199 for 3 weeks reversed chromosome hyperploidy in PreS2-LHBS cells and suppressed anchorage-independent growth of HBV-positive hepatoma cells. Together, this study identified ABT-199 as a negative modulator of PreS2-LHBS via mediating microautophagy. Our results indicate that long-term inhibition of PreS2-LHBS may serve as a novel strategy for the therapeutic prevention of HBV-mediated HCC.


Assuntos
Carcinoma Hepatocelular , Hepatite B Crônica , Neoplasias Hepáticas , Antígenos de Superfície , Antígenos de Superfície da Hepatite B/genética , Antígenos de Superfície da Hepatite B/metabolismo , Vírus da Hepatite B/genética , Humanos , Microautofagia
17.
Cells ; 11(12)2022 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-35741074

RESUMO

Autophagy is a pleiotropic and evolutionarily conserved process in eukaryotes that encompasses different types of mechanisms by which cells deliver cytoplasmic constituents to the lysosome for degradation. Interestingly, in mammals, two different and specialized autophagic pathways, (i) the chaperone-mediated autophagy (CMA) and (ii) the endosomal microautophagy (eMI), both rely on the use of the same cytosolic chaperone HSPA8 (also known as HSC70) for targeting specific substrates to the lysosome. However, this is not true for all organisms, and differences exist between species with respect to the coexistence of these two autophagic routes. In this paper, we present an in-depth analysis of the evolutionary history of the main components of CMA and eMI and discuss how the observed discrepancies between species may contribute to improving our knowledge of these two functions and their interplays.


Assuntos
Autofagia Mediada por Chaperonas , Animais , Autofagia , Lisossomos/metabolismo , Macroautofagia , Mamíferos , Microautofagia
18.
Biochem Biophys Res Commun ; 614: 161-168, 2022 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-35597153

RESUMO

Vacuoles and lysosomes are organelles involved in the degradation of cytoplasmic proteins and organelles. Vacuolar morphology is dynamically regulated by fission and fusion in budding yeast. Vacuolar fusion is elicited in nutrient-depleted conditions and mediated by inactivation of target of rapamycin complex 1 (TORC1) protein kinase. However, it is unknown whether and how vacuolar morphology affects macroautophagy and microautophagy, which are induced by nutrient starvation and TORC1 inactivation. Here, we developed a system to control vacuolar fission in budding yeast. Vacuolar fragmentation promoted microautophagy but not macroautophagy. Vacuolar fragmentation caused multiple nucleus-vacuole junctions. Multiple vacuoles caused by vacuolar fragmentation also improved micronucleophagy (microautophagic degradation of a portion of the nucleus). However, vacuolar morphology did not impact nucleolar remodeling, condensation of the rDNA (rRNA gene) region, or separation of ribosomal DNA from nucleolar proteins, which is evoked by TORC1 inactivation. Thus, this study provides insights into the impacts of vacuolar/lysosomal morphology on macroautophagy and microautophagy.


Assuntos
Macroautofagia , Microautofagia , Proteínas de Saccharomyces cerevisiae , Saccharomycetales , Vacúolos , Autofagia , DNA Ribossômico/genética , Macroautofagia/fisiologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Microautofagia/fisiologia , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomycetales/metabolismo , Vacúolos/metabolismo
19.
J Cell Sci ; 135(4)2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35099016

RESUMO

The proteasome is central to proteolysis by the ubiquitin-proteasome system under normal growth conditions but is itself degraded through macroautophagy under nutrient stress. A recently described AMP-activated protein kinase (AMPK)-regulated endosomal sorting complex required for transport (ESCRT)-dependent microautophagy pathway also regulates proteasome trafficking and degradation in low-glucose conditions in yeast. Aberrant proteasomes are more prone to microautophagy, suggesting the ESCRT system fine-tunes proteasome quality control under low-glucose stress. Here, we uncover additional features of the selective microautophagy of proteasomes in budding yeast. Genetic or pharmacological induction of aberrant proteasomes is associated with increased mono- or oligo-ubiquitylation of proteasome components, which appears to be recognized by ESCRT-0. AMPK controls this pathway in part by regulating the trafficking of ESCRT-0 to the vacuole surface, which also leads to degradation of the Vps27 subunit of ESCRT-0. The Rsp5 ubiquitin ligase contributes to proteasome subunit ubiquitylation, and multiple ubiquitin-binding elements in Vps27 are involved in their recognition. We propose that ESCRT-0 at the vacuole surface recognizes ubiquitylated proteasomes and initiates their microautophagic elimination during glucose depletion. This article has an associated First Person interview with the first author of the paper.


Assuntos
Microautofagia , Proteínas de Saccharomyces cerevisiae , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Ubiquitinação
20.
Autophagy ; 18(2): 443-448, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34643473

RESUMO

Nucleophagy, the selective subtype of autophagy that predominantly targets only a selected and (nonessential) portion of the nucleus, and rarely the nucleus in its entirety, for degradation, reinforces the paradigm that nucleophagy recycling is a meticulous and highly delicate process guarded by fail-safe mechanisms. Our goal in this commentary is to encourage autophagy researchers and other scientists to explore nucleophagy blind spots and gain advanced insights into the diverse roles of this process and its selective modality as they pertain to intranuclear quality control and cellular homeostasis. Identifying and deciphering nucleophagic signaling, regulation, molecular mechanism(s) and its mediators, cargo composition and nuclear membrane dynamics under numerous physiological and/or pathological settings will provide important advances in our understanding of this critical type of organelle-selective autophagy.Abbreviations: INM, inner nuclear membrane; LN, late nucleophagy; mRNA, messenger RNA; NE, nuclear envelope; NL, nuclear lamina; NPC(s), nuclear pore complex(es); NVJ(s), nucleus-vacuole junction(s); ONM, outer nuclear membrane; PMN, piecemeal microautophagy of the nucleus; PND, programmed nuclear death; PNuD, programmed nuclear destruction; rDNA/rRNA, ribosomal DNA/RNA.


Assuntos
Autofagia , Saccharomyces cerevisiae , Autofagia/fisiologia , Núcleo Celular/metabolismo , DNA Ribossômico/metabolismo , Microautofagia , Membrana Nuclear/metabolismo , Saccharomyces cerevisiae/metabolismo
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