All in the family: atypical Hsp70 chaperones are conserved modulators of Hsp70 activity

Shaner, Lance; Morano, Kevin A.

doi:10.1379/csc-245r.1

Cited by 84 publications

(89 citation statements)

References 61 publications

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“…Our results documenting cell integrity pathway phenotypes with SSE1 and STI1 mutants are completely consistent with these findings. In addition, with the recent assignment of Sse1 as an Hsp70 nucleotide exchange factor, we have been able to extend our investigation to show that Hsp70 NEF activity is required for both cell integrity signaling and morphogenesis (Dragovic et al 2006;Raviol et al 2006;Shaner et al 2006;Shaner and Morano 2007).…”

Section: Discussionsupporting

confidence: 52%

“…The Hsp110 class of eukaryotic chaperones is represented in budding yeast by the essential Sse1 and Sse2 proteins (Mukai et al 1993). Hsp110/Sse1 chaperones are divergent members of the Hsp70 superfamily, and recent work has established an unique role for this group as nucleotide exchange factors (NEFs) in a stable, heterodimeric complex with yeast and mammalian cytosolic Hsp70 chaperones (Shaner et al 2004(Shaner et al , 2006Yam et al 2005;Dragovic et al 2006;Raviol et al 2006;Shaner and Morano 2007). Sse1 was previously shown to be required for maturation and activity of Hsp90 substrates in yeast, consistent with a requirement for regulated transfer of client proteins from Hsp70 to Hsp90 in the early stages of the chaperone cycle (Liu et al 1999;Goeckeler et al 2002;Lee et al 2004).…”

Section: Introductionmentioning

confidence: 94%

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The Hsp110 protein chaperone Sse1 is required for yeast cell wall integrity and morphogenesis

Shaner¹,

Gibney²,

Morano³

2008

Curr Genet

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Molecular chaperones direct refolding and triage decisions and support signal transduction responses to cytotoxic stress. The eukaryotic chaperone Hsp110 is represented by the SSE1/2 genes in Saccharomyces cerevisiae, which act as nucleotide exchange factors (NEFs) for cognate cytosolic Hsp70 chaperones. In this report, we present evidence that Sse1 is required for signaling through the cell integrity pathway via partnership with Hsp90 and the terminal MAP kinase Slt2. We found that sse1Δ and sti1Δ mutant cells share the typical cell integrity mutant phenotypes of osmoremediated temperature-sensitive growth and sensitivity to cell wall-damaging agents. Sse1 binds to Slt2 in vivo and similar to Hsp90 mutants, Slt2 stability and phosphorylation is not compromised in sse1Δ cells, whereas activation of the downstream transcription factor Rlm1 is abolished. In addition to Rlm1, Slt2 activates the Swi4/Swi6 heterodimer SBF in response to cell wall damage. SSE1 displayed dramatic synthetic phenotypes when disrupted in combination with mutations in SBF and the related Mbp1/Swi6 heterodimer MBF, characterized by severe growth and morphological defects. These defects were reversed by restoration of Hsp70 NEF activity, providing a mechanistic model wherein Sse1 functionally partners with Hsp90 as an Hsp70 NEF to promote client protein maturation and interaction with downstream effectors.

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Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 94%

The Hsp110 protein chaperone Sse1 is required for yeast cell wall integrity and morphogenesis

Shaner¹,

Gibney²,

Morano³

2008

Curr Genet

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“…In our screen, we identified Ssz1p, a cytosolic member of the Hsp70 family. Ssz1p is tightly associated with the J-protein zuotin (Zuo1p) and the stable Zuo1p:Ssz1p complex (also known as the ribosome-associated complex, RAC) binds to the ribosome via Zuo1p, and, together with Ssbs, facilitates folding of nascent polypeptides as they exit the ribosome (Gautschi et al 2001;Hundley et al 2002;Gautschi et al 2002;Shaner and Morano 2007).…”

mentioning

confidence: 99%

Ssz1 Restores Endoplasmic Reticulum-Associated Protein Degradation in Cells Expressing Defective Cdc48–Ufd1–Npl4 Complex by Upregulating Cdc48

Bosis

Salomon²,

Ohayon³

et al. 2010

Genetics

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The endoplasmic reticulum (ER)-associated protein degradation (ERAD) pathway eliminates aberrant proteins from the ER. The key role of Cdc48p-Ufd1p-Npl4p is indicated by impaired ERAD in Saccharomyces cerevisiae with mutations in any of this complex's genes. We identified SSZ1 in genetic screens for cdc48-10 suppressors and show that it upregulates Cdc48p via the pleiotropic drug resistance (PDR) network. A pSSZ1 plasmid restored impaired ERAD-M of 6myc-Hmg2 in cdc48-10, ufd1-2, and npl4-1, while SSZ1 deletion had no effect. Ssz1p activates Pdr1p, the PDR master regulator. Indeed, plasmids of PDR1 or its target gene RPN4 increased cdc48-10p levels and restored ERAD-M in cdc48-10. Rpn4p regulates transcription of proteasome subunits and CDC48, thus RPN4 deletion abolished ERAD. However, the diminished proteasome level in Drpn4 was sufficient for degrading a cytosolic substrate, whereas the impaired ERAD-M was the result of diminished Cdc48p and was restored by expression of pCDC48. The corrected ERAD-M in the hypomorphic strains of the Cdc48 partners ufd1-2 and npl4-1 by the pCDC48 plasmid, and in cdc48-10 cells by the pcdc48-10 plasmid, combined with the finding that neither pSSZ1 nor pcdc48-10 restored ERAD-L of CPY*-HA, support our conclusion that Ssz1p suppressing effects is brought about by upregulating Cdc48p.

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“…Traditionally, Hsc70 has been reported to have roles in a variety of cellular functions, including protein folding, assembly, targeting, transport, and degradation (19,20). Many of the roles that Hsc70 plays in protein homeostasis have been well described, but recent studies are identifying a growing number of protein partners and are consequently revealing novel functions associated with heat shock proteins.…”

Section: Discussionmentioning

confidence: 99%

The Molecular Chaperone Hsc70 Interacts with Tyrosine Hydroxylase to Regulate Enzyme Activity and Synaptic Vesicle Localization

Parra¹,

Baust²,

Smith

et al. 2016

Journal of Biological Chemistry

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We previously reported that the vesicular monoamine transporter 2 (VMAT2) is physically and functionally coupled with Hsc70 as well as with the dopamine synthesis enzymes tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase, providing a novel mechanism for dopamine homeostasis regulation. Here we expand those findings to demonstrate that Hsc70 physically and functionally interacts with TH to regulate the enzyme activity and synaptic vesicle targeting. Co-immunoprecipitation assays performed in brain tissue and heterologous cells demonstrated that Hsc70 interacts with TH and aromatic amino acid decarboxylase. Furthermore, in vitro binding assays showed that TH directly binds the substrate binding and carboxyl-terminal domains of Hsc70. Immunocytochemical studies indicated that Hsc70 and TH co-localize in midbrain dopaminergic neurons. The functional significance of the Hsc70-TH interaction was then investigated using TH activity assays. In both dopaminergic MN9D cells and mouse brain synaptic vesicles, purified Hsc70 facilitated an increase in TH activity. Neither the closely related protein Hsp70 nor the unrelated Hsp60 altered TH activity, confirming the specificity of the Hsc70 effect. Overexpression of Hsc70 in dopaminergic MN9D cells consistently resulted in increased TH activity whereas knockdown of Hsc70 by short hairpin RNA resulted in decreased TH activity and dopamine levels. Finally, in cells with reduced levels of Hsc70, the amount of TH associated with synaptic vesicles was decreased. This effect was rescued by addition of purified Hsc70. Together, these data demonstrate a novel interaction between Hsc70 and TH that regulates the activity and localization of the enzyme to synaptic vesicles, suggesting an important role for Hsc70 in dopamine homeostasis.Dopaminergic neurons within the substantia nigra and ventral tegmental area are the primary sources of the catecholamine neurotransmitter dopamine (DA).2 Despite the fact that dopaminergic neurons account for less than 0.01% of all neurons, they play a significant role in brain function (1-3). Consequently, DA homeostasis is crucial for the preservation and regulation of physiological functions such as locomotion, cognition, neuroendocrine secretion, and motivated behaviors (4). Thus, it is not surprising that disruptions in the DA system have been implicated in several neurological and psychiatric disorders, including Parkinson disease, depression, schizophrenia, attention deficit hyperactivity disorder, Tourette syndrome, and drug addiction (4 -8).The DA life cycle consists of a series of highly regulated molecular events that are ultimately responsible for controlling DA homeostasis. Synthesis of DA occurs in the presynaptic terminals via two enzymatic reactions. First, tyrosine is converted into L-3,4-dihydroxyphenylalanine through the actions of the rate-limiting enzyme tyrosine hydroxylase (TH) (9, 10). Subsequently, aromatic amino acid decarboxylase (AADC) converts L-DOPA into DA (11). When synthesized, DA is packaged and stored withi...

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All in the family: atypical Hsp70 chaperones are conserved modulators of Hsp70 activity

Cited by 84 publications

References 61 publications

The Hsp110 protein chaperone Sse1 is required for yeast cell wall integrity and morphogenesis

The Hsp110 protein chaperone Sse1 is required for yeast cell wall integrity and morphogenesis

Ssz1 Restores Endoplasmic Reticulum-Associated Protein Degradation in Cells Expressing Defective Cdc48–Ufd1–Npl4 Complex by Upregulating Cdc48

The Molecular Chaperone Hsc70 Interacts with Tyrosine Hydroxylase to Regulate Enzyme Activity and Synaptic Vesicle Localization

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