Tying Everything Together: The Multiple Roles of Cysteine String Protein (CSP) in Regulated Exocytosis

Abstract

In addition to the core vesicle fusion machinery, the SNARE proteins, a large number of regulatory proteins have been implicated in the process of Ca 2+ -dependent exocytosis. How these exocytotic proteins are properly targeted and how their myriad interactions are temporally and spatially coordinated is poorly understood. Cysteine string protein (CSP), a secretory vesicle membrane protein and a member of the dnaJ family of co-chaperones, may assist in performing this function. Through its interaction with the ubiquitous chaperone, Hsc70, it is thought that cysteine string protein targets chaperone complexes to the exocytotic machinery to facilitate the correct folding of polypeptides or to regulate the assembly of protein complexes. Since its discovery, there have been conflicting reports from different systems concerned with whether cysteine string protein exerts its effects on exocytosis either up-or down-stream of Ca 2+ -influx. In this review, we summarize recent experiments that associate cysteine string protein with the regulation of vesicle filling, vesicle docking, Ca 2+ -channels and the SNARE proteins themselves, hence supporting a role for cysteine string protein as a multifunctional secretory co-chaperone. In addition, we provide an update on the mammalian isoforms of cysteine string protein following the recent discovery of two novel cysteine string proteins.

Enhancement of the Ca2+-triggering steps of native membrane fusion via thiol-reactivity

“…Furthermore, we cannot yet exclude the fact that IA may act on a protein that regulates a Ca 2+ sensor. Recently, several chaperones have been implicated in maintaining effective protein conformations or mediating the interactions of several exocytotic proteins [34][35][36]. Such a regulatory protein might even act through a negative clamp-like mechanism, such that blocking a disulfide interaction relieves inhibition of the Ca 2+ sensor.…”

Cysteine String Protein Monitors Late Steps in Cystic Fibrosis Transmembrane Conductance Regulator Biogenesis

“…In these systems, Csp overexpression blocks exocytosis (50 -52). An analogous block of CFTR trafficking may account for the effect of increased Csp on CFTR maturation; however, reducing Csp augmented CFTR maturation, whereas studies of neurosecretory processes indicate that Csp knockdown has the opposite effect, impairing exocytosis (53). These opposing actions of reduced Csp suggest that it plays different roles in exocytosis at the plasma membrane and in the early steps of CFTR biogenesis.…”

Characterization of the Gαs Regulator Cysteine String Protein

“…Most of the cysteine residues are palmitoylated and are required for membrane attachment to the secretory vesicle (7,8). In contrast to the conserved J domain, linker domain, and cysteine string regions, the C terminus diverges among CSP isoforms (9). CSP plays a crucial role in neurotransmitter release; however, its function is controversial.…”