Dataset Information

Gigaxonin E3 ligase governs ATG16L1 turnover to control autophagosome production.

ABSTRACT: Autophagy is an essential self-digestion machinery for cell survival and homoeostasis. Membrane elongation is fundamental, as it drives the formation of the double-membrane vesicles that engulf cytosolic material. LC3-lipidation, the signature of autophagosome formation, results from a complex ubiquitin-conjugating cascade orchestrated by the ATG16L1 protein, whose regulation is unknown. Here, we identify the Gigaxonin-E3 ligase as the first regulator of ATG16L1 turn-over and autophagosome production. Gigaxonin interacts with the WD40 domain of ATG16L1 to drive its ubiquitination and subsequent degradation. Gigaxonin depletion induces the formation of ATG16L1 aggregates and impairs LC3 lipidation, hence altering lysosomal fusion and degradation of the main autophagy receptor p62. Altogether, we demonstrate that the Gigaxonin-E3 ligase controls the production of autophagosomes by a reversible, ubiquitin-dependent process selective for ATG16L1. Our findings unveil the fundamental mechanisms of the control of autophagosome formation, and provide a molecular switch to fine-tune the activation of autophagy.

SUBMITTER: Scrivo A

PROVIDER: S-EPMC6377711 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Gigaxonin E3 ligase governs ATG16L1 turnover to control autophagosome production.

Scrivo Aurora A Codogno Patrice P Bomont Pascale P

Nature communications 20190215 1

Autophagy is an essential self-digestion machinery for cell survival and homoeostasis. Membrane elongation is fundamental, as it drives the formation of the double-membrane vesicles that engulf cytosolic material. LC3-lipidation, the signature of autophagosome formation, results from a complex ubiquitin-conjugating cascade orchestrated by the ATG16L1 protein, whose regulation is unknown. Here, we identify the Gigaxonin-E3 ligase as the first regulator of ATG16L1 turn-over and autophagosome produ ...[more]

PMID: 30770803

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Project description:Ubiquitination is a dynamic post-translational modification that regulates the fate of proteins and therefore modulates a myriad of cellular functions. At the last step of this sophisticated enzymatic cascade, E3 ubiquitin ligases selectively direct ubiquitin attachment to specific substrates. Altogether, the ?800 distinct E3 ligases, combined to the exquisite variety of ubiquitin chains and types that can be formed at multiple sites on thousands of different substrates confer to ubiquitination versatility and infinite possibilities to control biological functions. E3 ubiquitin ligases have been shown to regulate behaviors of proteins, from their activation, trafficking, subcellular distribution, interaction with other proteins, to their final degradation. Largely known for tagging proteins for their degradation by the proteasome, E3 ligases also direct ubiquitinated proteins and more largely cellular content (organelles, ribosomes, etc.) to destruction by autophagy. This multi-step machinery involves the creation of double membrane autophagosomes in which engulfed material is degraded after fusion with lysosomes. Cooperating in sustaining homeostasis, actors of ubiquitination, proteasome and autophagy pathways are impaired or mutated in wide range of human diseases. From initial discovery of pathogenic mutations in the E3 ligase encoding for E6-AP in Angelman syndrome and Parkin in juvenile forms of Parkinson disease, the number of E3 ligases identified as causal gene for neurological diseases has considerably increased within the last years. In this review, we provide an overview of these diseases, by classifying the E3 ubiquitin ligase types and categorizing the neurological signs. We focus on the Gigaxonin-E3 ligase, mutated in giant axonal neuropathy and present a comprehensive analysis of the spectrum of mutations and the recent biological models that permitted to uncover novel mechanisms of action. Then, we discuss the common functions shared by Gigaxonin and the other E3 ligases in cytoskeleton architecture, cell signaling and autophagy. In particular, we emphasize their pivotal roles in controlling multiple steps of the autophagy pathway. In light of the various targets and extending functions sustained by a single E3 ligase, we finally discuss the challenge in understanding the complex pathological cascade underlying disease and in designing therapeutic approaches that can apprehend this complexity.

Project description:As a highly dynamic organelle, mitochondria undergo constant fission and fusion to change their morphology and function, coping with various stress conditions. Loss of the balance between fission and fusion leads to impaired mitochondria function, which plays a critical role in the pathogenesis of Parkinson disease (PD). Yet the mechanisms behind mitochondria dynamics regulation remain to be fully illustrated. Chaperone-mediated autophagy (CMA) is a lysosome-dependent process that selectively degrades proteins to maintain cellular proteostasis. In this study, we demonstrated that MARCHF5, an E3 ubiquitin ligase required for mitochondria fission, is a CMA substrate. MARCHF5 interacted with key CMA regulators and was degraded by lysosomes. Severe oxidative stress compromised CMA activity and stabilized MARCHF5, which facilitated DNM1L translocation and led to excessive fission. Increase of CMA activity promoted MARCHF5 turnover, attenuated DNM1L translocation, and reduced mitochondria fragmentation, which alleviated mitochondrial dysfunction under oxidative stress. Furthermore, we showed that conditional expression of LAMP2A, the key CMA regulator, in dopaminergic (DA) neurons helped maintain mitochondria morphology and protected DA neuronal viability in a rodent PD model. Our work uncovers a critical role of CMA in maintaining proper mitochondria dynamics, and loss of this regulatory control may occur in PD and underlie its pathogenic process.Abbreviations: CMA: chaperone-mediated autophagy; DA: dopaminergic; DNM1L: dynamin 1 like; FCCP: carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone; HSPA8: heat shock protein family A (Hsp70) member 8; LAMP2A: lysosomal associated membrane protein 2A; MARCHF5: membrane-associated ring-CH-type finger 5; MMP: mitochondria membrane potential; OCR: oxygen consumption rate; 6-OHDA: 6-hydroxydopamine; PD: Parkinson disease; SNc: substantia nigra pars compacta; TEM: transmission electron microscopy; TH: tyrosine hydroxylase; TMRE: tetramethylrhodamine ethyl ester perchlorate; WT: wild type.

Dataset Information

Gigaxonin E3 ligase governs ATG16L1 turnover to control autophagosome production.

Publications

Gigaxonin E3 ligase governs ATG16L1 turnover to control autophagosome production.

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