A C. elegans model of human α1-antitrypsin deficiency links components of the RNAi pathway to misfolded protein turnover

被引：22

作者：

Long, Olivia S. ^{[1
,2
]}

Benson, Joshua A. ^{[1
,2
]}

Kwak, Joon Hyeok ^{[1
,2
]}

Luke, Cliff J. ^{[1
,2
]}

Gosai, Sager J. ^{[1
,2
]}

O'Reilly, Linda P. ^{[1
,2
]}

Wang, Yan ^{[1
,2
]}

Li, Jie ^{[1
,2
]}

Vetica, Anne C. ^{[1
,2
]}

Miedel, Mark T. ^{[1
,2
]}

Stolz, Donna B. ^{[3
]}

Watkins, Simon C. ^{[3
]}

Zuechner, Stephan ^{[4
,5
]}

Perlmutter, David H. ^{[1
,2
]}

Silverman, Gary A. ^{[1
,2
]}

Pak, Stephen C. ^{[1
,2
]}

机构：

[1] Univ Pittsburgh, Sch Med, Childrens Hosp Pittsburgh, UPMC,Dept Pediat, Pittsburgh, PA 15224 USA

[2] Magee Womens Hosp, Res Inst, Pittsburgh, PA 15224 USA

[3] Univ Pittsburgh, Sch Med, Ctr Biol Imaging, Pittsburgh, PA 15261 USA

[4] Univ Miami, Miller Sch Med, Dept Human Genet, Miami, FL 33136 USA

[5] Univ Miami, Miller Sch Med, Hussman Inst Human Genom, Miami, FL 33136 USA

来源：

HUMAN MOLECULAR GENETICS | 2014年 / 23卷 / 19期

基金：

美国国家卫生研究院;

关键词：

LIVER-DISEASE; ALPHA(1)-ANTITRYPSIN DEFICIENCY; ENDOPLASMIC-RETICULUM; MUTANT ALPHA(1)-ANTITRYPSIN-Z; ACCUMULATION; DEGRADATION; BINDING; GENES; ALPHA1-ANTITRYPSIN; PROTEOTOXICITY;

D O I：

10.1093/hmg/ddu235

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The accumulation of serpin oligomers and polymers within the endoplasmic reticulum (ER) causes cellular injury in patients with the classical form alpha 1-antitrypsin deficiency (ATD). To better understand the cellular and molecular genetic aspects of this disorder, we generated transgenic C. elegans strains expressing either thewild-type (ATM) or Z mutant form (ATZ) of the human serpin fused to GFP. Animals secreted ATM, but retained polymerized ATZ within dilated ER cisternae. These latter animals also showed slow growth, smaller brood sizes and decreased longevity; phenotypes observed in ATD patients or transgenic mouse lines expressing ATZ. Similar to mammalian models, ATZ was disposed of by autophagy and ER-associated degradation pathways. Mutant strains defective in insulin signaling (daf-2) also showed a marked decrease in ATZ accumulation. Enhanced ATZ turnover was associated with the activity of two proteins central to systemic/exogenous (exo)RNAi pathway: the dsRNA importer, SID-1 and the argonaute, RDE-1. Animals with enhanced exo-RNAi activity (rrf-3 mutant) phenocopied the insulin signaling mutants and also showed increased ATZ turnover. Taken together, these studies allude to the existence of a novel proteostasis pathway that mechanistically links misfolded protein turnover to components of the systemic RNAi machinery.

引用

页码：5109 / 5122

页数：14

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