Hsp70 clears misfolded kinases that partitioned into distinct quality-control compartments.
Hsp70 aids in protein folding and directs misfolded proteins to the cellular degradation machinery. We describe discrete roles of Hsp70,SSA1 as an important quality-control machinery that switches functions to ameliorate the cellular environment. SSA1 facilitates folding/maturation of newly synthesized protein kinases by aiding their phosphorylation process and also stimulates ubiquitylation and degradation of kinases in regular protein turnover or during stress when kinases are denatured or improperly folded. Significantly, while kinases accumulate as insoluble inclusions upon SSA1 inhibition, they form soluble inclusions upon Hsp90 inhibition or stress foci during heat stress. This suggests formation of inclusion-specific quality-control compartments under various stress conditions. Up-regulation of SSA1 results in complete removal of these inclusions by the proteasome. Elevation of the cellular SSA1 level accelerates kinase turnover and protects cells from proteotoxic stress. Upon overexpression, SSA1 targets heat-denatured kinases toward degradation, which could enable them to recover their functional state under physiological conditions. Thus active participation of SSA1 in the degradation of misfolded proteins establishes an essential role of Hsp70 in deciding client fate during stress.
Division of Molecular Medicine, Bose Institute, P-1/12 C.I.T. Scheme VIIM, Kolkata 700054, India.
Joydeep
J
Roy
Division of Molecular Medicine, Bose Institute, P-1/12 C.I.T. Scheme VIIM, Kolkata 700054, India.
Sahana
S
Mitra
Biophysics & Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF, Bidhannagar, Kolkata 700064, India.
Kaushik
K
Sengupta
Division of Molecular Medicine, Bose Institute, P-1/12 C.I.T. Scheme VIIM, Kolkata 700054, India mandalak@jcbose.ac.in.
Atin K
AK
Mandal
D000251:Adenosine Triphosphatases / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017510:Protein Folding; D059748:Proteolysis; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism* / Q000502:physiology*; D054875:Ubiquitination
D018840:HSP70 Heat-Shock Proteins; D029701:Saccharomyces cerevisiae Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; C457179:TPK2 protein, S cerevisiae; D020930:MAP Kinase Kinase Kinases; C067018:Ste11 protein, S cerevisiae; D000251:Adenosine Triphosphatases; C095973:SSA1 protein, S cerevisiae