HYPK

Official Full Name

huntingtin interacting protein K

Organism

Homo sapiens

GeneID

25764

Background

Enables protein folding chaperone. Involved in negative regulation of apoptotic process and protein stabilization. Located in cytoplasm; microtubule cytoskeleton; and nucleoplasm. Part of protein-containing complex. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

HSPC136; C15orf63;

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Detailed Information

Recent Research Progress

Huntingtin yeast partner K (HYPK), is a small chaperone-like protein, which can express in almost all human tissues. HYPK interacts with a variety of cytoplasmic and nuclear proteins, which signifies that HYPK may be involved in a variety of undetermined processes. In Caenorhabditis elegans, HYPK globally regulates the aging process by executing very important roles in cell stage specification and proteotoxicity.

HYPK can act as a global interacting partner-regulator of huntingtin97Qexon1, α-synuclein-A53T and superoxide dismutase1-G93A. The C-terminal hydrophobic region in the HIPK is in direct contact with the aggregates to initiate the formation of a chelate complex. HYPK aggregates by sensor in existing in a seeded amyloid-like state which also favors its own concentration-dependent self-reliance of HYPK leading to annular and non-fibrillar/amorphous aggregates. Two hydrophobic fragments are responsible for their own aggregation at the C-terminus of HYPK. Self-association of HYPK follows seed nucleation, in which oligomeric HYPK seeds nucleate HYPK shows differential interactions with aggregation-prone and non-aggregating proteins, as it preferentially binds to aggregation-prone proteins with higher affinity than native/non-aggregating proteins. In vivo, the HYPK chelate complexes prevents the formation of toxic protein aggregates and physiologically exhibits a positive effect on cell survival and normal cellular physiological recovery. Further investigation has revealed that HYPK is involved in diverse cellular processes and requires normal cellular functions.

HYPK plays a key role in huntington's disease (HD). So far as we know, HD is a polyglutamine expansion disorder, characterized by mutant HTT-mediated aggregate formation and cytotoxicity. The N-terminal 17 amino acid domain of HTT (HTT-N17) has an effect on N-terminal HTT subcellular localization, aggregate formation and subsequent pathogenicity of multiple Q-chains within the pathogenic range. HYPK is a HTT-interacting chaperone which can reduce N-terminal mutant HTT-mediated aggregate formation and cytotoxicity in neuronal cell lines. According to a recent research, specific interaction of HYPK with HTT-N17 is crucial for the chaperone activity of HYPK. Deletion of HTT-N17 leads to formation of tinier, SDS-soluble nuclear aggregates formed by N-terminal mutant HTT. The increased cytotoxicity imparted by these tiny aggregates might be contributed due to loss of interaction with HYPK. Furthermore, Choudhury K R, et al. confirmed that HYPK could also be involved in clearing mutant HTT aggregates by augmenting autophagy pathway as HYPK and its interacting partners augment autophagy.

It is worth mentioning that HYPK is a negative regulator of heat shock response. Heat shock response is an adaptive mechanism of cells characterized by up-regulation of heat shock proteins by heat-induced activation of heat shock factor 1 (HSF1). The transactivation ability of HSF1 is arrested upon restoration of proteostasis. HYPK has been identified as a heat-inducible protein and transcriptional target of HSF1. The related results showed that HYPK could act as negative regulator of heat shock response by repressing transcriptional activity of HSF1. As a repressor of heat shock response, HYPK can also inhibit HSF1-dependent trans-activation of its own promoter. The research further showed 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 the effective induction of HYPK in response to heat shock. Taken together, HYPK can suppress heat shock response via an auto-regulatory loop and downregulation of HYPK in HD, which caused by impaired transcriptional activity of HSF1 in presence of mutant huntingtin. In addition, HYPK is induced by cellular stress as well as transcriptional regulation of HSF1.

References:

Choudhury K R, et al. Chaperone protein HYPK interacts with the first 17 amino acid region of Huntingtin and modulates mutant HTT-mediated aggregation and cytotoxicity. Biochemical & Biophysical Research Communications, 2015, 456(1):66-73.
Choudhury K R, et al. Chaperone-like protein HYPK and its interacting partners augment autophagy. European Journal of Cell Biology, 2016, 95(6-7):182-194.
Ghosh D K, et al. Aggregation-prone regions in HYPK help it to form sequestration complex for toxic protein aggregates. Journal of Molecular Biology, 2018, 430(7).
Ghosh D K, et al. Disordered nanostructure in Huntingtin interacting protein K acts as stabilizing switch to prevent protein aggregation. Biochemistry, 2018, 57(13).
Das S, et al. Huntingtin interacting protein HYPK is a negative regulator of heat shock response and is downregulated in models of Huntington's disease. Experimental Cell Research, 2016, 343(2):107-117.

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