High p62 expression suppresses the NLRP1 inflammasome and increases stress resistance in cutaneous SCC cells.

NLRP1 is the primary inflammasome sensor in human keratinocytes. Sensing of UVB radiation by NLRP1 is believed to underlie the induction of sunburn. Although constitutive NLRP1 activation causes skin inflammation and predisposes patients to the development of cutaneous SCCs, the NLRP1 pathway is suppressed in established SCCs. Here, we identified high levels of the autophagy receptor p62 in SCC cells lines and SCC tumors. Increased NF-κB activity in SCC cells causes p62 up-regulation. Suppression of p62 expression rescues UVB-induced NLRP1 inflammasome activation in early-stage SCC cells. p62 expression protects SCC cells from cytotoxic drugs, whereas NLRP1 sensitizes them. In summary, we identify p62 as a novel negative regulator of the NLRP1 inflammasome in human cutaneous SCC cells, in which suppression of NLRP1 by increased levels of p62 supports stress resistance of skin cancer cells.