Unfolded protein response-induced ERdj3 secretion links ER stress to extracellular proteostasis

被引:113
作者
Genereux, Joseph C. [1 ,2 ]
Qu, Song [1 ,2 ,3 ]
Zhou, Minghai [4 ]
Ryno, Lisa M. [1 ,2 ]
Wang, Shiyu [5 ]
Shoulders, Matthew D. [2 ]
Kaufman, Randal J. [5 ]
Lasmezas, Corinne I. [4 ]
Kelly, Jeffery W. [1 ,2 ,6 ]
Wiseman, R. Luke [1 ,3 ]
机构
[1] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA
[2] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA
[3] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA
[4] Scripps Res Inst, Dept Infect Dis, Jupiter, FL USA
[5] Sanford Burnham Med Res Inst, Degenerat Dis Res Program, La Jolla, CA USA
[6] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA
关键词
ER stress; ERdj3; extracellular proteostasis; molecular chaperones; unfolded protein response; CENTRAL-NERVOUS-SYSTEM; QUALITY-CONTROL PROTEINS; GENOME-WIDE ASSOCIATION; CEREBROSPINAL-FLUID; MOLECULAR CHAPERONES; DISULFIDE-ISOMERASE; IDENTIFIES VARIANTS; PLASMA CLUSTERIN; DNAJ HOMOLOG; TRANSTHYRETIN;
D O I
10.15252/embj.201488896
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 Unfolded Protein Response (UPR) indirectly regulates extracellular proteostasis through transcriptional remodeling of endoplasmic reticulum (ER) proteostasis pathways. This remodeling attenuates secretion of misfolded, aggregation-prone proteins during ER stress. Through these activities, the UPR has a critical role in preventing the extracellular protein aggregation associated with numerous human diseases. Here, we demonstrate that UPR activation also directly influences extracellular proteostasis through the upregulation and secretion of the ER HSP40 ERdj3/ DNAJB11. Secreted ERdj3 binds misfolded proteins in the extracellular space, substoichiometrically inhibits protein aggregation, and attenuates proteotoxicity of disease-associated toxic prion protein. Moreover, ERdj3 can co-secrete with destabilized, aggregation-prone proteins in a stable complex under conditions where ER chaperoning capacity is overwhelmed, preemptively providing extracellular chaperoning of proteotoxic misfolded proteins that evade ER quality control. This regulated co-secretion of ERdj3 with misfolded clients directly links ER and extracellular proteostasis during conditions of ER stress. ERdj3 is, to our knowledge, the first metazoan chaperone whose secretion into the extracellular space is regulated by the UPR, revealing a new mechanism by which UPR activation regulates extracellular proteostasis.
引用
收藏
页码:4 / 19
页数:16
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