J protein mutations and resulting proteostasis collapse

Abstract

Despite a century of intensive investigation the effective treatment of protein aggregation diseases remains elusive. Ordinarily, molecular chaperones ensure that proteins maintain their functional conformation. The appearance of misfolded proteins that aggregate implies the collapse of the cellular chaperone quality control network. That said, the cellular chaperone network is extensive and functional information regarding the detailed action of specific chaperones is not yet available. J proteins (DnaJ/Hsp40) are a family of chaperone cofactors that harness Hsc70 (heat shock cognate protein of 70 kDa) for diverse conformational cellular tasks and, as such, represent novel clinically relevant targets for diseases resulting from the disruption of proteostasis. Here we review incisive reports identifying mutations in individual J protein chaperones and the proteostasis collapse that ensues.

The deubiquitinase ataxin-3 requires Rad23 and DnaJ-1 for its neuroprotective role in Drosophila melanogaster

“…DnaJ-1 is a member of the family of J/HSP40 proteins that function to provide client specificity and to stimulate ATPase activity of HSP70 chaperones (Kampinga and Craig, 2010; Koutras and Braun, 2014). DnaJ-1 suppresses retinal toxicity caused by a mutant fragment of the HD protein, huntingtin (Kazemi-Esfarjani and Benzer, 2000).…”

Evolution of an intricate J-protein network driving protein disaggregation in eukaryotes

“…In yeast, the J-domain of Tim14 (class C) forms a complex with the pseudo J-domain of Tim16 (class C) during mitochondrial protein import ( Mokranjac et al, 2006 ) and such JD-JD driven interactions may also exist among some J- or J-like proteins for specialized functions. Extensive biochemical and functional genomic approaches are now needed to fully understand the extent and regulation of this intricate J-protein network, especially in humans where J-protein targeted chaperone machineries are implicated in a wide range of pathologies including cancer, neurodegeneration, muscular atrophies, metabolic disorders and infectious diseases ( Koutras and Braun, 2014 ; Gibbs and Braun, 2008 ; Knox et al, 2011 ; Maier et al, 2008 ; Synofzik et al, 2014 ).…”

Auxilin facilitates membrane traffic in the early secretory pathway

“…This is of significant interest, because several mutations in DNAJC6, which encodes the nerve specific auxilin, were recently found to cause recessive juvenile parkinsonism. Mutations in DNAJ26, which encodes the ubiquitous auxilin GAK, are implicated in Parkinson’s disease susceptibility ( Koutras and Braun, 2014 ). It is speculated that such auxilin defects affect clathrin-mediated endocytosis at the synapse and thus dopamine receptor recycling.…”