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 Celljournal_title
Molecular biology of the cellauthors
Mathiowetz AJ,Baple E,Russo AJ,Coulter AM,Carrano E,Brown JD,Jinks RN,Crosby AH,Campellone KGdoi
10.1091/mbc.E17-01-0022subject
Has Abstractpub_date
2017-09-15 00:00:00pages
2492-2507issue
19eissn
1059-1524issn
1939-4586pii
mbc.E17-01-0022journal_volume
28pub_type
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