HSJ1 Is a Neuronal Shuttling Factor for the Sorting of Chaperone Clients to the Proteasome

Abstract

Protein degradation in eukaryotic cells usually involves the attachment of a ubiquitin chain to a substrate protein and its subsequent sorting to the proteasome. Molecular mechanisms underlying the sorting process only recently began to emerge and rely on a cooperation of chaperone machineries and ubiquitin-chain recognition factors [1-3]. Here, we identify isoforms of the cochaperone HSJ1 as neuronal shuttling factors for ubiquitylated proteins. HSJ1 combines a J-domain that stimulates substrate loading onto the Hsc70 chaperone with ubiquitin interaction motifs (UIMs) involved in binding ubiquitylated chaperone clients. HSJ1 prevents client aggregation, shields clients against chain trimming by ubiquitin hydrolases, and stimulates their sorting to the proteasome. In this way, HSJ1 isoforms participate in ER-associated degradation (ERAD) and protect neurons against cytotoxic protein aggregation.

Chaperone-assisted degradation: multiple paths to destruction

“…BAG-1 facilitates the docking of the complex at the proteasome, because it possesses a ubiquitin-like domain integrated in its primary structure, which is used for proteasome binding (Demand et al, 2001;Alberti et al, 2002). HSJ-1 belongs to the family of J-domain containing substrate-loading factors of Hsc/Hsp70 and in addition displays two ubiquitin interaction motifs that enable the co-chaperone to bind ubiquitylated chaperone clients after their initial encounter with CHIP (Westhoff et al, 2005; Figure 2). The combination of these activities allows HSJ-1 to facilitate the rebinding of ubiquitylated clients to Hsc/Hsp70 during sorting to the proteasome.…”

“…The combination of these activities allows HSJ-1 to facilitate the rebinding of ubiquitylated clients to Hsc/Hsp70 during sorting to the proteasome. In this way, the co-chaperone promotes the degradation of aggregation-prone forms of huntingtin in neuronal cells (Westhoff et al, 2005;Howarth et al, 2007). Another J-protein recently shown to facilitate CHIP-mediated degradation is the cysteine string protein (CSP), which is abundantly expressed in neurons, where it localizes to presynaptic junctions (Schmidt et al, 2009).…”

Molecular chaperones and neuronal proteostasis

“…HSJ1a can bind to ubiquitylated oligomers of Htt in the nucleus blocking the recruitment of more misfolded Htt and further aggregation, leading to increases in soluble Htt and potential autophagic clearance of cytoplasmic Htt oligomers [39]. HSJ1 also facilitates proteasomal degradation of Htt [37]. HSJ1a blocks the aggregation of mutant parkin and stimulates its refolding, so that parkin can function in mitochondrial quality control [95].…”

“…HSJ1 is alternatively spliced to produce two isoforms, HSJ1a and HSJ1b, with distinct intracellular localisations mediated by the C-terminal prenylation of the longer HSJ1b isoform [38]. Only the cytosolic and nuclear HSJ1a isoform was able to significantly reduce aggregation in a cellular model expressing polyQ huntingtin, highlighting that the localisation of chaperones is critical for their protective function [37]. The overexpression of HSJ1a was also shown to be neuroprotective in a R6/2 mouse model of HD [39].…”

“…1). HSJ1 contains an N-terminal J domain, a client binding domain and two ubiquitin interacting motifs (UIMs) [36,37]. The combination of these domains enables HSJ1 to target some client proteins for proteasomal degradation.…”