USP2 mediates HDAC6-dependent stabilization of HIPK2 and enhances its proapoptotic function

HIPK2 is a nuclear serine/threonine kinase that regulates development and cellular stress responses including DNA damage response. Previously we have shown that HDAC6 increases HIPK2 protein stability via UBP domain rather than its deacetylase activity. Here, we identify USP2 as a deubiquitinase that stabilizes HIPK2 by complexing to HDAC6 UBP. Overexpression of USP2 increased while its knockdown or chemical inhibition decreased the protein level of HIPK2. USP2 decreased the polyubiquitination of HIPK2, suggesting that USP2 is a HIPK2 deubiquitinase. We found evidence that HDAC6, USP2 and HIPK2 form complex in cells. Importantly, USP2 knockdown or chemical inhibition suppressed the HDAC6-mediated accumulation of HIPK2 protein. This indicates that the HDAC6-mediated HIPK2 regulation is USP2-dependent. Functionally, upregulation of HIPK2 by USP2 promoted the TNFα-induced cell death. Overall, our data suggest that USP2 increases HIPK2 protein stability and enhances its proapoptotic function.