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Introduction Hsc70 is a central molecular chaperone with fundamental physiological roles that range from uncoating clathrin-coated vesicles (Eisenberg and Greene 2007) to transport of proteins across mitochondrial membranes (Bhangoo et [...], Cysteine string protein (CSPα, also called DnaJC5) is unique among J proteins. Similar to other J proteins, CSPα interacts with and activates the ATPase of Hsc70s (heat shock proteins of 70 kDa), thereby harnessing the ATPase activity for conformational work on client proteins. In contrast to other J proteins, CSPα is anchored to synaptic vesicles, as well as to exocrine, endocrine and neuroendocrine secretory granules, and has been shown to have an essential anti-neurodegenerative role. CSPα-null organisms exhibit progressive neurodegeneration, behavioural deficits, and premature death, most likely due to the progressive misfolding of one or more client proteins. Here we highlight recent advances in our understanding of the critical role that CSPα plays in governing exocytotic secretory functions. Key words: CSPα, J protein, DnaJ protein, J domain, Hsp40, chaperone La CSPα (<< cysteine string protein >>, aussi appelee DnaJC5) est unique parmi les proteines J. Comme les autres proteines J, la CSPα interagit et active l'ATPase des Hsc70 (<< heat shock proteins of 70 kDa >>), controlant ainsi l'activite ATPase qui agit sur la conformation des proteines cibles. Mais contrairement aux autres proteines J, la CSPα est ancree dans les vesicules synaptiques, ainsi que dans les granules de secretion exocrines, endocrines et neuroendocrines, et elle joue un role anti-neurodegeneeratif essentiel. Les organismes deficients en CSPα montrent une neurodeegenerescence progressive, des defauts de comportements et un mort prematuree qui sont probablement dus au mauvais repliement progressif d'une ou de plusieurs proteines cibles. Nous mettons ici en evidence les recents progres dans notre connaissance du role cle joue; par la CSPα dans la regulation des fonctions secretaires lors de l'exocytose. Mots-cles: CSPα, proteines J, DnaJ, domaine J, Hsp40, chaperon [Traduit par la Redaction]

The heat shock protein 70 family members Hsc70 and Hsp70 are known to play a protective role against the onset of experimental pancreatitis, yet their molecular function in acini is unclear. Cysteine string protein (CSP-[alpha] is a zymogen granule (ZG) membrane protein characterized by an N[H.sub.2]-terminal 'J domain' and a central palmitoylated string of cysteine residues. The J domain functions as a cochaperone by modulating the activity of Hsc70/Hsp70 family members. A role for CSP-[alpha] in regulating digestive enzyme exocytosis from pancreas was investigated by introducing CSP-[alpha] truncations into isolated acini following their permeabilization with Perfringolysin O. Incubation of acini with CSP-[[alpha].sub.1-82], containing the J domain, significantly augmented [Ca.sup.2+]-stimulated amylase secretion. Effects of CSP-[[alpha].sub.1-82] were concentration dependent, with a maximum 80% increase occurring at 200 [micro]g/ml of protein. Although CSP-[[alpha].sub.1-82] had no effects on basal secretion measured in the presence of [less than or equal to] 10 nM free [Ca.sup.2+], it did significantly augment GTP-[gamma]S-induced secretion under basal [Ca.sup.2+] conditions by ~25%. Mutation of the J domain to abolish its cochaperone activity failed to augment [Ca.sup.2+]-stimulated secretion, implicating the CSP-[alpha]/Hsc70 cochaperone system as a regulatory component of the secretory pathway. CSP-[alpha] physically associates with vesicle-associated membrane protein 8 (VAMP 8) on ZGs, and the CSP-[alpha]-VAMP 8 interaction was dependent on amino acids 83-112 of CSP-[alpha]. Immunofluorescence analysis of acinar lobules or purified ZGs confirmed the CSP-[alpha] colocalization with VAMP 8. These data establish a role for CSP-[alpha] in regulating digestive enzyme secretion and suggest that CSP-[alpha] and Hsc70 modulate specific soluble N-ethylmaleimide-sensitive attachment receptor interactions necessary for exocytosis. heat shock protein 70; zymogen granules

Demonstrates that two separate regions of cysteine string proteins (CSP), secretory vesicle chaperones that are important for neurotransmitter release, associate with guanosine triphosphate-binding proteins (G proteins). Interaction of CSP with both heterotrimeric G proteins and N-type calcium channels; Role of distinct CSP binding sites in modulating G protein function and G protein inhibition of calcium channel.