A DNM2 Centronuclear Myopathy Mutation Reveals a Link between Recycling Endosome Scission and Autophagy

Puri, Claudia; Manni, Marco M.; Vicinanza, Mariella; Hilcenko, Christine; Zhu, Ye; Runwal, Gautam; Stamatakou, Eleanna; Menzies, Fiona M.; Mamchaoui, Kamel; Bitoun, Marc; Rubinsztein, David C.

doi:10.1016/j.devcel.2020.03.018

Cited by 31 publications

(26 citation statements)

References 47 publications

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“…Recycling endosomes are known to “feed” autophagosome by supplying membrane for autophagosome formation. 12 , 60 , 72 , 73 In this study, we identified the existence of CEMM on recycling endosomes ( Figures S3 A and S3B), which is consistent with previous report. 59 Second, we found this recycling endosomes-containing CEMMs provide a platform for the interaction between STX6 and VAMP3, which functions as barriers for VAMP3 activation and subsequent autophagosome formation ( Figures 3 , 4 , and 5 ).…”

Section: Discussionsupporting

confidence: 93%

Cholesterol-enriched membrane micro-domain deficiency induces doxorubicin resistance via promoting autophagy in breast cancer

Shi

et al. 2021

Molecular Therapy - Oncolytics

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Drug resistance has become one of the largest challenges for cancer chemotherapies. Under certain conditions, cancer cells hijack autophagy to cope with therapeutic stress, which largely undermines the chemo-therapeutic efficacy. Currently, biomarkers indicative of autophagy-derived drug resistance remain largely inclusive. Here, we report a novel role of lipid rafts/cholesterol-enriched membrane micro-domains (CEMMs) in autophagosome biogenesis and doxorubicin resistance in breast tumors. We showed that CEMMs are required for the interaction of VAMP3 with syntaxin 6 (STX6, a cholesterol-binding SNARE protein). Upon disruption of CEMM, VAMP3 is released from STX6, resulting in the trafficking of ATG16L1-containing vesicles to recycling endosomes and subsequent autophagosome biogenesis. Furthermore, we found that CEMM marker CAV1 is decreased in breast cancer patients and that the CEMM deficiency-induced autophagy is related to doxorubicin resistance, which is overcome by autophagy inhibition. Taken together, we propose a novel model whereby CEMMs in recycling endosomes support the VAMP3 and STX6 interaction and function as barriers to limit the activity of VAMP3 in autophagic vesicle fusion, thus CEMM deficiency promotes autophagosome biogenesis and doxorubicin resistance in breast tumors.

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Section: Discussionsupporting

confidence: 93%

Cholesterol-enriched membrane micro-domain deficiency induces doxorubicin resistance via promoting autophagy in breast cancer

Shi

et al. 2021

Molecular Therapy - Oncolytics

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“…Expression of the temperature sensitive mutant of DNM1 (dynamin 1 G273D , dyn ts ) in HeLa cells causes defects in transferring recycling [ 207 ]. Recently, DNM2 was shown to be a crucial player in a process relevant for muscle tissue: triggering the scission and release of autophagosome precursors from recycling endosomes [ 113 ], a critical step for autophagy described in more detail in the section on protein homeostasis.…”

Section: Common Pathomechanisms Of Cnmsmentioning

confidence: 99%

“…DNM2 was also found to locate specifically on recycling endosomes where it binds LC3 and regulates the release of autophagosome precursors. This process is impaired with the R465W mutation, which sequesters DNM2 at the plasma membrane where it binds ISTN1 at endocytic sites [ 113 ]. BIN1 mutations and deficiency may also affect the autophagy pathway, as increased p62 staining was described in BIN1-related ADCNM muscles [ 5 ].…”

Section: Common Pathomechanisms Of Cnmsmentioning

confidence: 99%

Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances

Gómez-Oca

Cowling²,

Laporte

2021

IJMS

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Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and structural defects including fiber hypotrophy and organelle mispositioning. The main CNM forms are caused by mutations in: the MTM1 gene encoding the phosphoinositide phosphatase myotubularin (myotubular myopathy), the DNM2 gene encoding the mechanoenzyme dynamin 2, the BIN1 gene encoding the membrane curvature sensing amphiphysin 2, and the RYR1 gene encoding the skeletal muscle calcium release channel/ryanodine receptor. MTM1, BIN1, and DNM2 proteins are involved in membrane remodeling and trafficking, while RyR1 directly regulates excitation-contraction coupling (ECC). Several CNM animal models have been generated or identified, which confirm shared pathological anomalies in T-tubule remodeling, ECC, organelle mispositioning, protein homeostasis, neuromuscular junction, and muscle regeneration. Dynamin 2 plays a crucial role in CNM physiopathology and has been validated as a common therapeutic target for three CNM forms. Indeed, the promising results in preclinical models set up the basis for ongoing clinical trials. Another two clinical trials to treat myotubular myopathy by MTM1 gene therapy or tamoxifen repurposing are also ongoing. Here, we review the contribution of the different CNM models to understanding physiopathology and therapy development with a focus on the commonly dysregulated pathways and current therapeutic targets.

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“…The Atg9 vesicle, which is a transport vesicle in which the Atg9 protein resides, is further suggested to constitute a part of the autophagosome [52], although the other possibility is also discussed [51]. The involvement of recycling endosome derived vesicles has also been reported [53]. Future studies are needed to understand the full repertoire of the lipid source of the autophagosome membrane.…”

Section: Main Textmentioning

confidence: 99%

Autophagosome formation in relation to the endoplasmic reticulum

Yamamoto

Noda

2020

J Biomed Sci

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Autophagy is a process in which a myriad membrane structures called autophagosomes are formed de novo in a single cell, which deliver the engulfed substrates into lysosomes for degradation. The size of the autophagosomes is relatively uniform in non-selective autophagy and variable in selective autophagy. It has been recently established that autophagosome formation occurs near the endoplasmic reticulum (ER). In this review, we have discussed recent advances in the relationship between autophagosome formation and endoplasmic reticulum. Autophagosome formation occurs near the ER subdomain enriched with phospholipid synthesizing enzymes like phosphatidylinositol synthase (PIS)/CDP-diacylglycerol-inositol 3-phosphatidyltransferase (CDIPT) and choline/ethanolamine phosphotransferase 1 (CEPT1). Autophagy-related protein 2 (Atg2), which is involved in autophagosome formation has a lipid transfer capacity and is proposed to directly transfer the lipid molecules from the ER to form autophagosomes. Vacuole membrane protein 1 (VMP1) and transmembrane protein 41b (TMEM41b) are ER membrane proteins that are associated with the formation of the subdomain. Recently, we have reported that an uncharacterized ER membrane protein possessing the DNAJ domain, called ERdj8/DNAJC16, is associated with the regulation of the size of autophagosomes. The localization of ERdj8/DNAJC16 partially overlaps with the PIS-enriched ER subdomain, thereby implying its association with autophagosome size determination.

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A DNM2 Centronuclear Myopathy Mutation Reveals a Link between Recycling Endosome Scission and Autophagy

Cited by 31 publications

References 47 publications

Cholesterol-enriched membrane micro-domain deficiency induces doxorubicin resistance via promoting autophagy in breast cancer

Cholesterol-enriched membrane micro-domain deficiency induces doxorubicin resistance via promoting autophagy in breast cancer

Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances

Autophagosome formation in relation to the endoplasmic reticulum

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