Suppression of polyglutamine protein toxicity by co-expression of a heat-shock protein 40 and a heat-shock protein 110

Y Kuo,S Ren,B A Edgar,U Lao,T Wang

doi:10.1038/cddis.2013.351

Abstract

A network of heat-shock proteins mediates cellular protein homeostasis, and has a fundamental role in preventing aggregation-associated neurodegenerative diseases. In a Drosophila model of polyglutamine (polyQ) disease, the HSP40 family protein, DNAJ-1, is a superior suppressor of toxicity caused by the aggregation of polyQ containing proteins. Here, we demonstrate that one specific HSP110 protein, 70 kDa heat-shock cognate protein cb (HSC70cb), interacts physically and genetically with DNAJ-1 in vivo, and that HSC70cb is necessary for DNAJ-1 to suppress polyglutamine-induced cell death in Drosophila. Expression of HSC70cb together with DNAJ-1 significantly enhanced the suppressive effects of DNAJ-1 on polyQ-induced neurodegeneration, whereas expression of HSC70cb alone did not suppress neurodegeneration in Drosophila models of either general polyQ disease or Huntington's disease. Furthermore, expression of a human HSP40, DNAJB1, together with a human HSP110, APG-1, protected cells from polyQ-induced neural degeneration in flies, whereas expression of either component alone had little effect. Our data provide a functional link between HSP40 and HSP110 in suppressing the cytotoxicity of aggregation-prone proteins, and suggest that HSP40 and HSP110 function together in protein homeostasis control.

Highlights

Molecular chaperones are involved in several key cellular functions, including the suppression of protein aggregation, folding of nascent proteins, refolding of denatured proteins, and translocation of proteins.[4,5] The majority of chaperones are referred to as heat-shock proteins (HSPs), and they participate in various protein folding and refolding events through ATP-dependent binding and release cycles.[6]
HSP110 forms high–molecularweight complexes with HSP70, and facilitates the nucleotide exchange of HSP70.21–24 Recent reports suggested that HSP110 associated with protein aggregation and introducing HSP110 prevented the toxicity of aggregation-prone proteins.[25,26,27,28]
In Drosophila models of polyQ disease, the HSP40 family protein DNAJ-1 was identified as a potent suppressor of aggregation and the associated toxicity of polyQ proteins.[10,11,31]

Summary

Introduction

Molecular chaperones are involved in several key cellular functions, including the suppression of protein aggregation, folding of nascent proteins, refolding of denatured proteins, and translocation of proteins.[4,5] The majority of chaperones are referred to as heat-shock proteins (HSPs), and they participate in various protein folding and refolding events through ATP-dependent binding and release cycles.[6]. Higher eukaryotes have a variety of HSP40 family members to regulate the substrate specificity of chaperones.[9] A few types of HSP40 proteins have been shown to dramatically suppress toxicity in polyQ disease models.[10,11,12,13,14,15] Overexpression of HSP70 or combination of HSP70 and HSP40 reduced aggregate formation and provided cellular protection, suggesting that HSP70 and HSP40 might function together in chaperoning aggregation-prone proteins.[14,16,17]. We Received 14.5.13; revised 29.7.13; accepted 12.8.13; Edited by D Bano found that introducing human homologs of DNAJ-1 and HSC70cb, DNAJB1 and APG-1, suppressed the cytotoxicity of polyQ proteins including mutated huntingtin. Our results provide the basis for the development of an HSP40- and HSP110-related therapy for polyQ diseases

Methods

Results

Conclusion