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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Puri, Claudia 
Manni, Marco M 
Vicinanza, Mariella 
Hilcenko, Christine  ORCID logo  https://orcid.org/0000-0002-9596-7833
Zhu, Ye 

Abstract

Autophagy involves engulfment of cytoplasmic contents by double-membraned autophagosomes, which ultimately fuse with lysosomes to enable degradation of their substrates. We recently proposed that the tubular-vesicular recycling endosome membranes were a core platform on which the critical early events of autophagosome formation occurred, including LC3-membrane conjugation to autophagic precursors. Here, we report that the release of autophagosome precursors from recycling endosomes is mediated by DNM2-dependent scission of these tubules. This process is regulated by DNM2 binding to LC3 and is increased by autophagy-inducing stimuli. This scission is defective in cells expressing a centronuclear-myopathy-causing DNM2 mutant. This mutant has an unusual mechanism as it depletes normal-functioning DNM2 from autophagosome formation sites on recycling endosomes by causing increased binding to an alternative plasma membrane partner, ITSN1. This "scission" step is, thus, critical for autophagosome formation, is defective in a human disease, and influences the way we consider how autophagosomes are formed.

Description

Keywords

DNM2, ITSN1, RAB11, autophagosome, autophagy, centronuclear myopathy, phagophore, recycling endosome, Adaptor Proteins, Vesicular Transport, Autophagosomes, Autophagy, Cell Membrane, Dynamin II, Endosomes, HeLa Cells, Humans, Lysosomes, Microtubule-Associated Proteins, Mutation, Myopathies, Structural, Congenital, Protein Transport

Journal Title

Dev Cell

Conference Name

Journal ISSN

1534-5807
1878-1551

Volume Title

53

Publisher

Elsevier BV
Sponsorship
MRC (MR/T012412/1)