An Amish founder mutation disrupts a PI(3)P-WHAMM-Arp2/3 complex-driven autophagosomal remodeling pathway.

Abstract:

:Actin nucleation factors function to organize, shape, and move membrane-bound organelles, yet they remain poorly defined in relation to disease. Galloway-Mowat syndrome (GMS) is an inherited disorder characterized by microcephaly and nephrosis resulting from mutations in the WDR73 gene. This core clinical phenotype appears frequently in the Amish, where virtually all affected individuals harbor homozygous founder mutations in WDR73 as well as the closely linked WHAMM gene, which encodes a nucleation factor. Here we show that patient cells with both mutations exhibit cytoskeletal irregularities and severe defects in autophagy. Reintroduction of wild-type WHAMM restored autophagosomal biogenesis to patient cells, while inactivation of WHAMM in healthy cell lines inhibited lipidation of the autophagosomal protein LC3 and clearance of ubiquitinated protein aggregates. Normal WHAMM function involved binding to the phospholipid PI(3)P and promoting actin nucleation at nascent autophagosomes. These results reveal a cytoskeletal pathway controlling autophagosomal remodeling and illustrate several molecular processes that are perturbed in Amish GMS patients.

journal_name

Mol Biol Cell

authors

Mathiowetz AJ,Baple E,Russo AJ,Coulter AM,Carrano E,Brown JD,Jinks RN,Crosby AH,Campellone KG

doi

10.1091/mbc.E17-01-0022

subject

Has Abstract

pub_date

2017-09-15 00:00:00

pages

2492-2507

issue

19

eissn

1059-1524

issn

1939-4586

pii

mbc.E17-01-0022

journal_volume

28

pub_type

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