Cysteine string protein (CSP) is an insulin secretory granule-associated protein regulating beta -cell exocytosis

Brown, Hilary F.; Larsson, Olof; Bränström, Robert; Yang, Shao Nian; Leibiger, Barbara; Leibiger, Ingo B.; Fried, Gabriel; Moede, Tilo; Deeney, Jude T.; Brown, G. R.; Jacobsson, Gunilla; Rhodes, Christopher J.; Braun, Janice E. A.; Scheller, Richard H.; Corkey, Barbara E.; Berggren, Per Olof; Meister, Björn

doi:10.1093/emboj/17.17.5048

Cited by 87 publications

(95 citation statements)

References 52 publications

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“…Instead, in the absence of CSP␣, the calyx synapse developed an age-dependent functional impairment, consistent with a role for CSP␣ as part of a molecular chaperone that makes it possible for synapses to keep running for extended time periods (2). Although this hypothesis was in agreement with previous observations in CSP-deficient flies (4), alternative hypotheses about the function of CSP were proposed based on the phenotype of CSP-deficient flies and on biochemical studies of protein-protein interactions mediated by CSP (7)(8)(9)(10)(11)(12)(13)(14).…”

supporting

confidence: 77%

CSPα-deficiency causes massive and rapid photoreceptor degeneration

Schmitz

Tabares²,

Khimich³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Cysteine string protein (CSP) ␣ is an abundant synaptic vesicle protein that contains a DNA-J domain characteristic of Hsp40-type cochaperones. Previous studies showed that deletion of CSP␣ in mice leads to massive lethal neurodegeneration but did not clarify how the neurodegeneration affects specific subpopulations of neurons. Here, we analyzed the effects of the CSP␣ deficiency on tonically active ribbon synapses of the retina and the inner ear. We show that CSP␣-deficient photoreceptor terminals undergo dramatic and rapidly progressive neurodegeneration that starts before eye opening and initially does not affect other retinal synapses. These changes are associated with progressive blindness. In contrast, ribbon synapses of auditory hair cells did not exhibit presynaptic impairments in CSP␣-deficient mice. Hair cells, but not photoreceptor cells or central neurons, express CSP␤, thereby accounting for the lack of a hair-cell phenotype in CSP␣ knockout mice. Our data demonstrate that tonically active ribbon synapses in retina are particularly sensitive to the deletion of CSP␣ and that expression of at least one CSP isoform is essential to protect such tonically active synapses from neurodegeneration.hair cell ͉ ribbon synapse ͉ electroretinogram ͉ chaperone ͉ blindness S ynaptic vesicle exo-and endocytosis is mediated by a sophisticated machinery that allows nerve terminals to operate at high speed (1). Such continuous membrane traffic requires specific mechanisms to deal with the use-dependent aging and denaturation of proteins. One such mechanism may involve the synaptic vesicle protein cysteine string protein (CSP) ␣ that is thought to function as a cochaperone in presynaptic terminals (2, 3).CSP␣ is an abundant presynaptic protein (4) that contains a string of cysteine residues and a DNA-J domain that functionally collaborates with the DNA-K domains of Hsc70 proteins (reviewed in refs. 5 and 6). CSP␣ activates the ATPase activity of Hsc70 (7,8) and forms a trimeric complex with Hsc70 and the tetratricopeptide repeat protein SGT (3). This complex catalyzes the ATP-dependent refolding of denatured luciferase (3). Invertebrates have a single CSP gene, whereas mammals express three CSP genes: CSP␣ that is widely distributed but highly enriched in brain, and CSP␤ and CSP␥ that are primarily found in testis (2).Analyses of knockout (KO) mice revealed that CSP␣-deficient mice are relatively normal at birth but exhibit a progressive lethal phenotype that results in death after 2-4 months (2). Recordings in the Calyx of Held synapse of CSP␣ KO mice documented that CSP␣ is not required for N-, P͞Q-, and R-type Ca 2ϩ -channel function or Ca 2ϩ -triggered vesicle exocytosis. Instead, in the absence of CSP␣, the calyx synapse developed an age-dependent functional impairment, consistent with a role for CSP␣ as part of a molecular chaperone that makes it possible for synapses to keep running for extended time periods (2). Although this hypothesis was in agreement with previous observations in CSP-deficient flies (4), alt...

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supporting

confidence: 77%

CSPα-deficiency causes massive and rapid photoreceptor degeneration

Schmitz

Tabares²,

Khimich³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…These findings demonstrate a crucial role for Csp in neurosecretion (22). In neurons, Csp is associated predominantly with synaptic vesicles (19), and in secretory cells it is found in large dense core or secretory granules (23,24). Studies of membrane dye labeling (25) and neurotransmitter release (26,27) indicated that Csp knockouts exhibit defective neurotransmitter exocytosis; presynaptic endocytosis and vesicle recycling appear to be intact.…”

mentioning

confidence: 89%

Cysteine String Protein Interacts with and Modulates the Maturation of the Cystic Fibrosis Transmembrane Conductance Regulator

Zhang

Peters

Sun

et al. 2002

Journal of Biological Chemistry

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The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated chloride channel whose phosphorylation regulates both channel gating and its trafficking at the plasma membrane. Cysteine string proteins (Csps) are J-domain-containing, membrane-associated proteins that have been functionally implicated in regulated exocytosis. Therefore, we evaluated the possibility that Csp is involved in regulated CFTR trafficking. We found Csp expressed in mammalian epithelial cell lines, several of which express CFTR. In Calu-3 airway cells, immunofluorescence colocalized Csp with calnexin in the endoplasmic reticulum and with CFTR at the apical membrane domain. CFTR coprecipitated with Csp from Calu-3 cell lysates. Csp associated with both core-glycosylated immature and fully glycosylated mature CFTRs (bands B and C); however, in relation to the endogenous levels of the B and C bands expressed in Calu-3 cells, the Csp interaction with band B predominated. In vitro protein binding assays detected physical interactions of both mammalian Csp isoforms with the CFTR R-domain and the N terminus, having submicromolar affinities. In Xenopus oocytes expressing CFTR, Csp overexpression decreased the chloride current and membrane capacitance increases evoked by cAMP stimulation and decreased the levels of CFTR protein detected by immunoblot. In mammalian cells, the steady-state expression of CFTR band C was eliminated, and pulse-chase studies showed that Csp coexpression blocked the conversion of immature to mature CFTR and stabilized band B. These results demonstrate a primary role for Csp in CFTR protein maturation. The physical interaction of this Hsc70-binding protein with immature CFTR, its localization in the endoplasmic reticulum, and the decrease in production of mature CFTR observed during Csp overexpression reflect a role for Csp in CFTR biogenesis. The documented role of Csp in regulated exocytosis, its interaction with mature CFTR, and its coexpression with CFTR at the apical membrane domain of epithelial cells may reflect also a role for Csp in regulated CFTR trafficking at the plasma membrane.

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“…In fact, although it is clear that CSP plays a significant component in neurotransmission (10,13), its precise role is not yet established. Current reports support a role for CSP in (i) the regulation of exocytosis (41)(42)(43)(44)(45), (ii) the regulation of Ca 2ϩ transmembrane fluxes (46 -51), and (iii) the regulation of folding/refolding of synaptic proteins (13,14). Given that the contributions of vesicular and plasma membrane G␣ s in the various experimental models utilized are not known, it is possible that differences in G␣ s signaling cascades underlie some of the differences observed among these reports.…”

Section: Csp Stimulates Steady-state Hydrolysis Of Gtp By G␣ S -Tomentioning

confidence: 99%

Characterization of the Gαs Regulator Cysteine String Protein

Natochin

Campbell

Barren

et al. 2005

Journal of Biological Chemistry

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Cysteine string protein (CSP) is an abundant regulated secretory vesicle protein that is composed of a string of cysteine residues, a linker domain, and an Nterminal J domain characteristic of the DnaJ/Hsp40 cochaperone family. We have shown previously that CSP associates with heterotrimeric GTP-binding proteins (G proteins) and promotes G protein inhibition of N-type Ca 2؉ channels. To elucidate the mechanisms by which CSP modulates G protein signaling, we examined the effects of CSP 1-198 (full-length), CSP 1-112 , and CSP 1-82 on the kinetics of guanine nucleotide exchange and GTP hydrolysis. In this report, we demonstrate that CSP selectively interacts with G␣ s and increases steady-state GTP hydrolysis. CSP 1-198 modulation of G␣ s was dependent on Hsc70 (70-kDa heat shock cognate protein) and SGT (small glutamine-rich tetratricopeptide repeat domain protein), whereas modulation by CSP 1-112 was Hsc70-SGT-independent. CSP 1-112 preferentially associated with the inactive GDP-bound conformation of G␣ s . Consistent with the stimulation of GTP hydrolysis, CSP 1-112 increased guanine nucleotide exchange of G␣ s. The interaction of native G␣ s and CSP was confirmed by coimmunoprecipitation and showed that G␣ s associates with CSP. Furthermore, transient expression of CSP in HEK cells increased cellular cAMP levels in the presence of the ␤ 2 adrenergic agonist isoproterenol. Together, these results demonstrate that CSP modulates G protein function by preferentially targeting the inactive GDP-bound form of G␣ s and promoting GDP/GTP exchange. Our results show that the guanine nucleotide exchange activity of full-length CSP is, in turn, regulated by Hsc70-SGT.G proteins constitute a family of heterotrimeric GTP-binding proteins that act as transducers in a variety of transmembrane signaling systems. G proteins are composed of ␣, ␤, and ␥ subunits that dissociate into G␣ and G␤␥ upon activation. Activation of G proteins involves an exchange of GDP for GTP on G␣ subunits and the release of GTP-bound G␣ and G␤␥ to interact with effector molecules. Effector molecules include adenylate cyclase, phospholipases, phosphodiesterases, and ion channels. Several modulators of G proteins have been identified and are thought to play crucial roles in the kinetics of G protein signaling (e.g. guanine nucleotide exchange factors (GEFs), 1 guanine nucleotide dissociation inhibitors, and GTPase-activating proteins). Our previous work has identified cysteine string protein (CSP) as a novel modulator of G proteins (1-3). Although the functional parallels between CSP and established G protein modulators are evident, the molecular mechanism by which CSP regulates G proteins is not yet known.CSPs are secretory vesicle proteins of 34 kDa that contain three conserved domains: a J domain, a linker domain, and a cysteine string region (Fig. 1A). The J domain is a 70-amino acid region of homology shared by DnaJ (a well characterized bacterial co-chaperone) and many otherwise unrelated eukaryotic proteins. The linker domain is a 30-amino acid ...

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Cysteine string protein (CSP) is an insulin secretory granule-associated protein regulating beta -cell exocytosis

Abstract: 5048

Cited by 87 publications

References 52 publications

CSPα-deficiency causes massive and rapid photoreceptor degeneration

CSPα-deficiency causes massive and rapid photoreceptor degeneration

Cysteine String Protein Interacts with and Modulates the Maturation of the Cystic Fibrosis Transmembrane Conductance Regulator

Characterization of the Gαs Regulator Cysteine String Protein

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