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Article ; Online: A TRIM32-AMBRA1-ULK1 complex initiates the autophagy response in atrophic muscle cells.

Di Rienzo, Martina / Piacentini, Mauro / Fimia, Gian Maria

2019 Volume 15, Issue 9, Page(s) 1674–1676

Abstract: The Ser/Thr protein kinase ULK1 is an upstream macroautophagy/autophagy regulator that is rapidly activated to ensure a proper adaptive response to stress conditions. Signaling pathways modulating ULK1 activity have been extensively characterized in ... ...

Abstract	The Ser/Thr protein kinase ULK1 is an upstream macroautophagy/autophagy regulator that is rapidly activated to ensure a proper adaptive response to stress conditions. Signaling pathways modulating ULK1 activity have been extensively characterized in response to nutrient/energy shortage, which mainly act by mediating ULK1 post-translational modifications, such as phosphorylation, acetylation and ubiquitination. Less characterized is how tissue-specific stress signals are able to activate ULK1 to induce autophagy. Our recent study has uncovered the E3 ubiquitin ligase TRIM32 as a novel ULK1 activator that regulates autophagy in muscle cells upon atrophy induction. TRIM32 is conveyed to ULK1 by the autophagy cofactor AMBRA1 to stimulate its kinase activity through unanchored K63-linked polyubiquitin chains. Notably, mutations in TRIM32 responsible for limb-girdle muscular dystrophy 2H disrupt its ability to bind ULK1 and to induce autophagy in muscle cells, resulting in a dysregulated activation of the atrophic process. In conclusion, we have identified a novel molecular mechanism by which autophagy is regulated in muscles, whose alteration is associated with the development of muscular dystrophy.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Atrophy ; Autophagy ; Autophagy-Related Protein-1 Homolog ; Humans ; Intracellular Signaling Peptides and Proteins ; Muscular Dystrophies, Limb-Girdle ; Transcription Factors ; Tripartite Motif Proteins ; Ubiquitin-Protein Ligases ; Ubiquitination
Chemical Substances	AMBRA1 protein, human ; Adaptor Proteins, Signal Transducing ; Intracellular Signaling Peptides and Proteins ; Transcription Factors ; Tripartite Motif Proteins ; TRIM32 protein, human (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Autophagy-Related Protein-1 Homolog (EC 2.7.11.1) ; ULK1 protein, human (EC 2.7.11.1)
Language	English
Publishing date	2019-06-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.1080/15548627.2019.1635385
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Article ; Online: TRIM proteins in autophagy: selective sensors in cell damage and innate immune responses.

Di Rienzo, Martina / Romagnoli, Alessandra / Antonioli, Manuela / Piacentini, Mauro / Fimia, Gian Maria

Cell death and differentiation

2020 Volume 27, Issue 3, Page(s) 887–902

Abstract: Autophagy, a main intracellular catabolic process, is induced in response to a variety of cellular stresses to promptly degrade harmful agents and to coordinate the activity of prosurvival and prodeath processes in order to determine the fate of the ... ...

Abstract	Autophagy, a main intracellular catabolic process, is induced in response to a variety of cellular stresses to promptly degrade harmful agents and to coordinate the activity of prosurvival and prodeath processes in order to determine the fate of the injured cells. While the main components of the autophagy machinery are well characterized, the molecular mechanisms that confer selectivity to this process both in terms of stress detection and cargo engulfment have only been partly elucidated. Here, we discuss the emerging role played by the E3 ubiquitin ligases of the TRIM family in regulating autophagy in physiological and pathological conditions, such as inflammation, infection, tumorigenesis, and muscle atrophy. TRIM proteins employ different strategies to regulate the activity of the core autophagy machinery, acting either as scaffold proteins or via ubiquitin-mediated mechanisms. Moreover, they confer high selectivity to the autophagy-mediated degradation as described for the innate immune response, where TRIM proteins mediate both the engulfment of pathogens within autophagosomes and modulate the immune response by controlling the stability of signaling regulators. Importantly, the elucidation of the molecular mechanisms underlying the regulation of autophagy by TRIMs is providing important insights into how selective types of autophagy are altered under pathological conditions, as recently shown in cancer and muscular dystrophy.
MeSH term(s)	Animals ; Autophagy ; Cells/pathology ; Humans ; Immunity, Innate ; Models, Biological ; Signal Transduction ; Tripartite Motif Proteins/metabolism
Chemical Substances	Tripartite Motif Proteins
Language	English
Publishing date	2020-01-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1225672-9
ISSN	1476-5403 ; 1350-9047
ISSN (online)	1476-5403
ISSN	1350-9047
DOI	10.1038/s41418-020-0495-2
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Zs.A 4230: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: The ubiquitin ligase TRIM32 promotes the autophagic response to Mycobacterium tuberculosis infection in macrophages.

Romagnoli, Alessandra / Di Rienzo, Martina / Petruccioli, Elisa / Fusco, Carmela / Palucci, Ivana / Micale, Lucia / Mazza, Tommaso / Delogu, Giovanni / Merla, Giuseppe / Goletti, Delia / Piacentini, Mauro / Fimia, Gian Maria

Cell death & disease

2023 Volume 14, Issue 8, Page(s) 505

Abstract: Mycobacterium tuberculosis (Mtb) is known to evade host immune responses and persist in macrophages for long periods. A mechanism that the host uses to combat Mtb is xenophagy, a selective form of autophagy that targets intracellular pathogens for ... ...

Abstract	Mycobacterium tuberculosis (Mtb) is known to evade host immune responses and persist in macrophages for long periods. A mechanism that the host uses to combat Mtb is xenophagy, a selective form of autophagy that targets intracellular pathogens for degradation. Ubiquitination of Mtb or Mtb-containing compartments is a key event to recruit the autophagy machinery and mediate the bacterial delivery to the lysosome. This event relies on the coordinated and complementary activity of different ubiquitin ligases, including PARKIN, SMURF1, and TRIM16. Because each of these factors is responsible for the ubiquitination of a subset of the Mtb population, it is likely that additional ubiquitin ligases are employed by macrophages to trigger a full xenophagic response during Mtb infection. In this study, we investigated the role TRIM proteins whose expression is modulated in response to Mtb or BCG infection of primary macrophages. These TRIMs were ectopically expressed in THP1 macrophage cell line to assess their impact on Mtb replication. This screening identified TRIM32 as a novel player involved in the intracellular response to Mtb infection, which promotes autophagy-mediated Mtb degradation. The role of TRIM32 in xenophagy was further confirmed by silencing TRIM32 expression in THP1 cells, which causes increased intracellular growth of Mtb associated to impaired Mtb ubiquitination, reduced recruitment of the autophagy proteins NDP52/CALCOCO2 and BECLIN 1/BECN1 to Mtb and autophagosome formation. Overall, these findings suggest that TRIM32 plays an important role in the host response to Mtb infection through the induction of autophagy, representing a promising target for host-directed tuberculosis therapies.
MeSH term(s)	Humans ; Ubiquitin/metabolism ; Macrophages/metabolism ; Tuberculosis/genetics ; Autophagy/physiology ; Mycobacterium tuberculosis ; Tripartite Motif Proteins/genetics ; Tripartite Motif Proteins/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Transcription Factors/metabolism
Chemical Substances	Ubiquitin ; TRIM16 protein, human (EC 2.3.2.27) ; Tripartite Motif Proteins ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; TRIM32 protein, human (EC 2.3.2.27) ; Transcription Factors ; SMURF1 protein, human (EC 2.3.2.26)
Language	English
Publishing date	2023-08-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-023-06026-1
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Article ; Online: A microRNA Arising from the Negative Strand of SARS-CoV-2 Genome Targets FOS to Reduce AP-1 Activity.

Greco, Francesco / Lorefice, Elisa / Carissimi, Claudia / Laudadio, Ilaria / Ciccosanti, Fabiola / Di Rienzo, Martina / Colavita, Francesca / Meschi, Silvia / Maggi, Fabrizio / Fimia, Gian Maria / Fulci, Valerio

Non-coding RNA

2023 Volume 9, Issue 3

Abstract: Virus-encoded microRNAs were first reported in the Epstein-Barr virus in 2004. Subsequently, a few hundred viral miRNAs have been identified, mainly in DNA viruses belonging to ... ...

Abstract	Virus-encoded microRNAs were first reported in the Epstein-Barr virus in 2004. Subsequently, a few hundred viral miRNAs have been identified, mainly in DNA viruses belonging to the
Language	English
Publishing date	2023-05-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2813993-8
ISSN	2311-553X ; 2311-553X
ISSN (online)	2311-553X
ISSN	2311-553X
DOI	10.3390/ncrna9030033
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Article ; Online: AMBRA1 regulates mitophagy by interacting with ATAD3A and promoting PINK1 stability.

Di Rienzo, Martina / Romagnoli, Alessandra / Ciccosanti, Fabiola / Refolo, Giulia / Consalvi, Veronica / Arena, Giuseppe / Valente, Enza Maria / Piacentini, Mauro / Fimia, Gian Maria

Autophagy

2021 Volume 18, Issue 8, Page(s) 1752–1762

Abstract: PINK1 accumulation at the outer mitochondrial membrane (OMM) is a key event required to signal depolarized mitochondria to the autophagy machinery. How this early step is, in turn, modulated by autophagy proteins remains less characterized. Here, we show ...

Abstract	PINK1 accumulation at the outer mitochondrial membrane (OMM) is a key event required to signal depolarized mitochondria to the autophagy machinery. How this early step is, in turn, modulated by autophagy proteins remains less characterized. Here, we show that, upon mitochondrial depolarization, the proautophagic protein AMBRA1 is recruited to the OMM and interacts with PINK1 and ATAD3A, a transmembrane protein that mediates mitochondrial import and degradation of PINK1. Downregulation of AMBRA1 expression results in reduced levels of PINK1 due to its enhanced degradation by the mitochondrial protease LONP1, which leads to a decrease in PINK1-mediated ubiquitin phosphorylation and mitochondrial PRKN/PARKIN recruitment. Notably, ATAD3A silencing rescues defective PINK1 accumulation in AMBRA1-deficient cells upon mitochondrial damage. Overall, our findings underline an upstream contribution of AMBRA1 in the control of PINK1-PRKN mitophagy by interacting with ATAD3A and promoting PINK1 stability. This novel regulatory element may account for changes of PINK1 levels in neuropathological conditions.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Autophagy ; Carbonyl Cyanide m-Chlorophenyl Hydrazone/pharmacology ; Mitochondria/metabolism ; Mitophagy ; Protein Kinases/metabolism ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	AMBRA1 protein, human ; Adaptor Proteins, Signal Transducing ; Carbonyl Cyanide m-Chlorophenyl Hydrazone (555-60-2) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Protein Kinases (EC 2.7.-)
Language	English
Publishing date	2021-11-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.1080/15548627.2021.1997052
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Article: Emerging Mechanisms in Initiating and Terminating Autophagy.

Antonioli, Manuela / Di Rienzo, Martina / Piacentini, Mauro / Fimia, Gian Maria

Trends in biochemical sciences

2017 Volume 42, Issue 1, Page(s) 28–41

Abstract: Autophagy is a major degradative process activated in a rapid and transient manner to cope with stress conditions. Whether autophagy is beneficial or detrimental depends upon the rate of induction and the appropriateness of the duration. Alterations in ... ...

Abstract	Autophagy is a major degradative process activated in a rapid and transient manner to cope with stress conditions. Whether autophagy is beneficial or detrimental depends upon the rate of induction and the appropriateness of the duration. Alterations in both autophagy initiation and termination predispose the cell to death, and affect the execution of other inducible processes such as inflammation. In this review we discuss how stress signaling pathways dynamically control the activity of the autophagy machinery by mediating post-translational modifications and regulatory protein interactions. In particular, we highlight the emerging role of TRIM and CULLIN families of ubiquitin ligases which play opposite roles in the autophagy response by promoting or inhibiting, respectively, the activity of the autophagy initiation complex.
MeSH term(s)	Animals ; Autophagy/physiology ; Humans ; Protein Processing, Post-Translational ; Signal Transduction ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2017-01
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	194216-5
ISSN	1362-4326 ; 0968-0004 ; 0376-5067
ISSN (online)	1362-4326
ISSN	0968-0004 ; 0376-5067
DOI	10.1016/j.tibs.2016.09.008
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Article ; Online: Proteomic analysis identifies the RNA helicase DDX3X as a host target against SARS-CoV-2 infection.

Ciccosanti, Fabiola / Di Rienzo, Martina / Romagnoli, Alessandra / Colavita, Francesca / Refolo, Giulia / Castilletti, Concetta / Agrati, Chiara / Brai, Annalaura / Manetti, Fabrizio / Botta, Lorenzo / Capobianchi, Maria Rosaria / Ippolito, Giuseppe / Piacentini, Mauro / Fimia, Gian Maria

Antiviral research

2021 Volume 190, Page(s) 105064

Abstract: COVID-19 is currently a highly pressing health threat and therapeutic strategies to mitigate the infection impact are urgently needed. Characterization of the SARS-CoV-2 interactome in infected cells may represent a powerful tool to identify cellular ... ...

Abstract	COVID-19 is currently a highly pressing health threat and therapeutic strategies to mitigate the infection impact are urgently needed. Characterization of the SARS-CoV-2 interactome in infected cells may represent a powerful tool to identify cellular proteins hijacked by viruses for their life cycle and develop host-oriented antiviral therapeutics. Here we report the proteomic characterization of host proteins interacting with SARS-CoV-2 Nucleoprotein in infected Vero E6 cells. We identified 24 high-confidence proteins mainly playing a role in RNA metabolism and translation, including RNA helicases and scaffold proteins involved in the formation of stress granules, cytoplasmic aggregates of messenger ribonucleoproteins that accumulate as a result of stress-induced translation arrest. Analysis of stress granules upon SARS-CoV-2 infection showed that these structures are not induced in infected cells, neither eIF2α phosphorylation, an upstream event leading to stress-induced translation inhibition. Notably, we found that G3BP1, a stress granule component that associates with the Nucleoprotein, is required for efficient SARS-CoV-2 replication. Moreover, we showed that the Nucleoprotein-interacting RNA helicase DDX3X colocalizes with viral RNA foci and its inhibition by small molecules or small interfering RNAs significantly reduces viral replication. Altogether, these results indicate that SARS-CoV-2 subverts the stress granule machinery and exploits G3BP1 and DDX3X for its replication cycle, offering groundwork for future development of host-directed therapies.
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; COVID-19/metabolism ; COVID-19/virology ; Cell Line ; Chlorocebus aethiops ; DEAD-box RNA Helicases/metabolism ; DNA Helicases ; Eukaryotic Initiation Factor-2/metabolism ; Host-Pathogen Interactions ; Humans ; Poly-ADP-Ribose Binding Proteins/genetics ; Poly-ADP-Ribose Binding Proteins/metabolism ; Proteomics/methods ; RNA Helicases ; RNA Recognition Motif Proteins/metabolism ; RNA, Small Interfering/metabolism ; RNA, Viral/metabolism ; SARS-CoV-2/metabolism ; Vero Cells ; Virus Replication/physiology ; COVID-19 Drug Treatment
Chemical Substances	Antiviral Agents ; Eukaryotic Initiation Factor-2 ; Poly-ADP-Ribose Binding Proteins ; RNA Recognition Motif Proteins ; RNA, Small Interfering ; RNA, Viral ; DDX3X protein, human (EC 3.6.1.-) ; DNA Helicases (EC 3.6.4.-) ; G3BP1 protein, human (EC 3.6.4.12) ; DEAD-box RNA Helicases (EC 3.6.4.13) ; RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2021-03-26
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2021.105064
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Article ; Online: On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2.

Sauvat, Allan / Ciccosanti, Fabiola / Colavita, Francesca / Di Rienzo, Martina / Castilletti, Concetta / Capobianchi, Maria Rosaria / Kepp, Oliver / Zitvogel, Laurence / Fimia, Gian Maria / Piacentini, Mauro / Kroemer, Guido

Cell death & disease

2020 Volume 11, Issue 8, Page(s) 656

Abstract: The current epidemic of coronavirus disease-19 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) calls for the development of inhibitors of viral replication. Here, we performed a bioinformatic analysis of published and ... ...

Abstract	The current epidemic of coronavirus disease-19 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) calls for the development of inhibitors of viral replication. Here, we performed a bioinformatic analysis of published and purported SARS-CoV-2 antivirals including imatinib mesylate that we found to suppress SARS-CoV-2 replication on Vero E6 cells and that, according to the published literature on other coronaviruses is likely to act on-target, as a tyrosine kinase inhibitor. We identified a cluster of SARS-CoV-2 antivirals with characteristics of lysosomotropic agents, meaning that they are lipophilic weak bases capable of penetrating into cells. These agents include cepharentine, chloroquine, chlorpromazine, clemastine, cloperastine, emetine, hydroxychloroquine, haloperidol, ML240, PB28, ponatinib, siramesine, and zotatifin (eFT226) all of which are likely to inhibit SARS-CoV-2 replication by non-specific (off-target) effects, meaning that they probably do not act on their 'official' pharmacological targets, but rather interfere with viral replication through non-specific effects on acidophilic organelles including autophagosomes, endosomes, and lysosomes. Imatinib mesylate did not fall into this cluster. In conclusion, we propose a tentative classification of SARS-CoV-2 antivirals into specific (on-target) versus non-specific (off-target) agents based on their physicochemical characteristics.
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Betacoronavirus/physiology ; COVID-19 ; Cell Death/drug effects ; Chlorocebus aethiops ; Coronavirus Infections/metabolism ; Coronavirus Infections/virology ; Drug Evaluation, Preclinical/methods ; Hydroxychloroquine/pharmacology ; Imatinib Mesylate/pharmacology ; Lysosomes/drug effects ; Pandemics ; Pneumonia, Viral/metabolism ; Pneumonia, Viral/virology ; Protein Kinase Inhibitors/pharmacology ; RNA, Viral/drug effects ; SARS-CoV-2 ; Vero Cells ; Viral Load/drug effects ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; Protein Kinase Inhibitors ; RNA, Viral ; Hydroxychloroquine (4QWG6N8QKH) ; Imatinib Mesylate (8A1O1M485B)
Keywords	covid19
Language	English
Publishing date	2020-08-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-020-02842-x
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Article ; Online: Negative Regulation of Mitochondrial Antiviral Signaling Protein-Mediated Antiviral Signaling by the Mitochondrial Protein LRPPRC During Hepatitis C Virus Infection.

Refolo, Giulia / Ciccosanti, Fabiola / Di Rienzo, Martina / Basulto Perdomo, Ariel / Romani, Marta / Alonzi, Tonino / Tripodi, Marco / Ippolito, Giuseppe / Piacentini, Mauro / Fimia, Gian Maria

Hepatology (Baltimore, Md.)

2018 Volume 69, Issue 1, Page(s) 34–50

Abstract: Hepatitis C virus (HCV) is highly efficient in establishing a chronic infection, having evolved multiple strategies to suppress the host antiviral responses. The HCV nonstructural 5A (NS5A) protein, in addition to its role in viral replication and ... ...

Abstract	Hepatitis C virus (HCV) is highly efficient in establishing a chronic infection, having evolved multiple strategies to suppress the host antiviral responses. The HCV nonstructural 5A (NS5A) protein, in addition to its role in viral replication and assembly, has long been known to hamper the interferon (IFN) response. However, the mechanism of this inhibitory activity of NS5A remains partly characterized. In a functional proteomic screening carried out in HCV replicon cells, we identified the mitochondrial protein LRPPRC as an NS5A binding factor. Notably, we found that downregulation of LRPPRC expression results in a significant inhibition of HCV infection, which is associated with an increased activation of the IFN response. Moreover, we showed that LRPPRC acts as a negative regulator of the mitochondrial-mediated antiviral immunity, by interacting with mitochondrial antiviral signaling protein (MAVS) and inhibiting its association with TRAF3 and TRAF6. Finally, we demonstrated that NS5A is able to interfere with MAVS activity in a LRPPRC-dependent manner. Conclusion: Overall, our results indicate that NS5A contributes to the inhibition of innate immune pathways during HCV infection by exploiting the ability of LRPPRC to inhibit MAVS-regulated antiviral signaling.
MeSH term(s)	Adaptor Proteins, Signal Transducing/physiology ; Cells, Cultured ; Hepacivirus/physiology ; Hepatitis C, Chronic/virology ; Humans ; Mitochondrial Proteins/physiology ; Neoplasm Proteins/physiology ; Signal Transduction ; Viral Nonstructural Proteins/physiology
Chemical Substances	Adaptor Proteins, Signal Transducing ; LRPPRC protein, human ; MAVS protein, human ; Mitochondrial Proteins ; Neoplasm Proteins ; Viral Nonstructural Proteins ; NS-5 protein, hepatitis C virus (EC 2.7.7.48)
Language	English
Publishing date	2018-12-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604603-4
ISSN	1527-3350 ; 0270-9139
ISSN (online)	1527-3350
ISSN	0270-9139
DOI	10.1002/hep.30149
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Article: TRIM50 regulates Beclin 1 proautophagic activity.

Fusco, Carmela / Mandriani, Barbara / Di Rienzo, Martina / Micale, Lucia / Malerba, Natascia / Cocciadiferro, Dario / Sjøttem, Eva / Augello, Bartolomeo / Squeo, Gabriella Maria / Pellico, Maria Teresa / Jain, Ashish / Johansen, Terje / Fimia, Gian Maria / Merla, Giuseppe

Biochimica et biophysica acta. Molecular cell research

2018 Volume 1865, Issue 6, Page(s) 908–919

Abstract: Autophagy is a catabolic process needed for maintaining cell viability and homeostasis in response to numerous stress conditions. Emerging evidence indicates that the ubiquitin system has a major role in this process. TRIMs, an E3 ligase protein family, ... ...

Abstract	Autophagy is a catabolic process needed for maintaining cell viability and homeostasis in response to numerous stress conditions. Emerging evidence indicates that the ubiquitin system has a major role in this process. TRIMs, an E3 ligase protein family, contribute to selective autophagy acting as receptors and regulators of the autophagy proteins recognizing endogenous or exogenous targets through intermediary autophagic tags, such as ubiquitin. Here we report that TRIM50 fosters the initiation phase of starvation-induced autophagy and associates with Beclin1, a central component of autophagy initiation complex. We show that TRIM50, via the RING domain, ubiquitinates Beclin 1 in a K63-dependent manner enhancing its binding with ULK1 and autophagy activity. Finally, we found that the Lys-372 residue of TRIM50, critical for its own acetylation, is necessary for its E3 ligase activity that governs Beclin1 ubiquitination. Our study expands the roles of TRIMs in regulating selective autophagy, revealing an acetylation-ubiquitination dependent control for autophagy modulation.
MeSH term(s)	Acetylation ; Animals ; Autophagy ; Autophagy-Related Protein-1 Homolog/genetics ; Autophagy-Related Protein-1 Homolog/metabolism ; Beclin-1/genetics ; Beclin-1/metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Tripartite Motif Proteins/genetics ; Tripartite Motif Proteins/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination
Chemical Substances	BECN1 protein, human ; Beclin-1 ; Becn1 protein, mouse ; Intracellular Signaling Peptides and Proteins ; Membrane Proteins ; Tripartite Motif Proteins ; TRIM50 protein, human (EC 2.3.2.27) ; TRIM50 protein, mouse (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Autophagy-Related Protein-1 Homolog (EC 2.7.11.1) ; ULK1 protein, human (EC 2.7.11.1) ; Ulk1 protein, mouse (EC 2.7.11.1)
Language	English
Publishing date	2018-03-29
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0167-4889 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0167-4889 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbamcr.2018.03.011
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