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A disease-associated frameshift mutation in caveolin-1 disrupts caveolae
formation and function through introduction of a de novo ER retention signal.
Authors Copeland CA, Han B, Tiwari A, Austin ED, Loyd JE, West JD, Kenworthy AK
Submitted By Submitted Externally on 11/9/2017
Status Published
Journal Molecular biology of the cell
Year 2017
Date Published 11/1/2017
Volume : Pages 28 : 3095 - 3111
PubMed Reference 28904206
Abstract Caveolin-1 (CAV1) is an essential component of caveolae and is implicated in
numerous physiological processes. Recent studies have identified heterozygous
mutations in the CAV1 gene in patients with pulmonary arterial hypertension
(PAH), but the mechanisms by which these mutations impact caveolae assembly and
contribute to disease remain unclear. To address this question, we examined the
consequences of a familial PAH-associated frameshift mutation in CAV1,
P158PfsX22, on caveolae assembly and function. We show that C-terminus of the
CAV1 P158 protein contains a functional ER-retention signal that inhibits ER
exit and caveolae formation and accelerates CAV1 turnover in Cav1(-/-) MEFs.
Moreover, when coexpressed with wild-type (WT) CAV1 in Cav1(-/-) MEFs, CAV1-P158
functions as a dominant negative by partially disrupting WT CAV1 trafficking. In
patient skin fibroblasts, CAV1 and caveolar accessory protein levels are
reduced, fewer caveolae are observed, and CAV1 complexes exhibit biochemical
abnormalities. Patient fibroblasts also exhibit decreased resistance to a
hypo-osmotic challenge, suggesting the function of caveolae as membrane
reservoir is compromised. We conclude that the P158PfsX22 frameshift introduces
a gain of function that gives rise to a dominant negative form of CAV1, defining
a new mechanism by which disease-associated mutations in CAV1 impair caveolae


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