title: Huntingtin interacting protein HYPK is a negative regulator of heat shock response and is downregulated in models of Huntington's Disease.
abstract: Huntingtin interacting protein HYPK (Huntingtin Yeast Partner K) is an intrinsically unstructured protein having chaperone-like activity and can suppress mutant huntingtin aggregates and toxicity in cell model of Huntington's Disease (HD). Heat shock response is an adaptive mechanism of cells characterized by upregulation of heat shock proteins by heat-induced activation of heat shock factor 1 (HSF1). The trans-activation ability of HSF1 is arrested upon restoration of proteostasis. We earlier identified HYPK as a heat-inducible protein and transcriptional target of HSF1. Here we show that HYPK can act as negative regulator of heat shock response by repressing transcriptional activity of HSF1. As part of its role as a repressor of heat shock response, HYPK can also inhibit HSF1-dependent trans-activation of its own promoter. HYPK is downregulated in cell and animal model of HD. We further show that transcriptional downregulation of HYPK in HD cell model is a consequence of reduced occupancy of HSF1 in HYPK promoter. Moreover, presence of mutant huntingtin inhibits effective induction of HYPK in response to heat shock. Taken together, our findings reveal that HYPK can suppress heat shock response via an autoregulatory loop and downregulation of HYPK in HD is caused by impaired transcriptional activity of HSF1 in presence of mutant huntingtin.
authors.affiliation: Crystallography & Molecular Biology Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India. Electronic address: mail2srijit@gmail.com.
authors.forename: Srijit
authors.initials: S
authors.lastname: Das
authors.affiliation: Crystallography & Molecular Biology Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India; Biomedical Genomics Centre, PG Polyclinic Building (3rd floor), 5, Suburbun Hospital Road, Kolkata 700020, India. Electronic address: nitai_sinp@yahoo.com.
authors.forename: Nitai Pada
authors.initials: NP
authors.lastname: Bhattacharyya
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics*; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response; D006801:Humans; D000071058:Huntingtin Protein / Q000378:metabolism*; D006816:Huntington Disease / Q000378:metabolism*; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015203:Reproducibility of Results; D013696:Temperature; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; C526912:HYPK protein, human; C581869:HYPK protein, mouse; D000076249:Heat Shock Transcription Factors; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D014157:Transcription Factors
keywords: Heat shock factor 1; Heat shock response; Huntingtin Yeast Partner K; Huntington's Disease