Huntingtin interacting protein HYPK is a negative regulator of heat shock response and is downregulated in models of Huntington's Disease

• HYPK inhibits heat shock response.
• HYPK regulates its own expression.
• HYPK is downregulated in Huntington's Disease models.
• HSF1 occupancy in HYPK promoter is altered in HD cell model.
• Mutant huntingtin inhibits heat shock response.

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.