P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and virus infection

Abstract

Inflammasomes integrate cytosolic evidence of infection or damage to mount inflammatory responses. The inflammasome sensor NLRP1 is expressed in human keratinocytes and coordinates inflammation in the skin. We found that diverse stress signals converge on the activation of p38 kinases to initiate human NLRP1 inflammasome assembly: UV irradiation and microbial molecules that initiate the ribotoxic stress response critically relied on the MAP3 kinase ZAKα to activate p38 and ultimately human NLRP1. Infection with insect-transmitted alphaviruses, including Semliki Forest, Ross River, and Chikungunya virus, also activated NLRP1 in a p38-dependent manner. In the absence on ZAKα, inflammasome assembly was maintained, although at reduced levels, indicating contribution of other upstream kinases. NLRP1 activation by direct nanobody-mediated ubiquitination was independent of p38 activity. Stimulation of p38 by overexpression of MAP2 kinases MKK3 or MKK6 is sufficient for NLRP1 activation, and NLRP1 is directly phosphorylated by p38. Taken together, we define p38 activation as a unifying signaling hub that controls NLRP1 inflammasome activation by integrating a variety of cellular stress signals relevant to the skin.

ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome

“…We have expanded the repertoire of known human NLRP1 agonists to include multiple microbial ribotoxins such as ANS and DON. The same results have been independently reported by a concurrent study ( 40 ). Our work raises several questions to be addressed by future studies.…”

Ubiquitination as a key regulatory mechanism for O3-induced cutaneous redox inflammasome activation

“…Oxidized cysteine can then be targeted for arginilation and be degraded via the Arg/N-end rule pathway, that it is therefore considered as a NO/O 2 sensor pathway involved in the elimination of misfolded proteins [ 81 ]. In addition, other PTMs events have been reported to modulate NLRP1 since MAPK kinases ZAKα, p38 and c-Jun N-terminal kinase (JNK) could induce NLRP1 activation via phosphorylation, particularly in response to UV radiations [ [82] , [83] , [84] ]. This evidence may suggest a similar mechanism for O 3 that has been found to modulate these kinases especially in the airway inflammatory response [ [85] , [86] , [87] ].…”

NLRP1 in Cutaneous SCCs: An Example of the Complex Roles of Inflammasomes in Cancer Development

“…UVB-induced NLRP1 activation requires the activity of the stress-induced protein kinases p38 and JNK [ 113 ]. Recently, it was shown that this is induced by the kinase ZAKα (leucine-zipper and sterile-alpha motif kinase) [ 114 , 115 ] upon activation of the ribotoxic stress response (RSR) pathway [ 116 ] ( Figure 2 ). The RSR is induced by the collision of ribosomes upon UVB radiation and sensed by ZAKα binding directly to the ribosomes.…”

“…Then, ZAKα is activated, inducing phosphorylation of p38 and JNK. Finally, activated ZAKα and p38 directly activate NLRP1 by phosphorylation [ 114 , 115 ]. In non-stressed cells, NLRP1 is inhibited upon binding to DPP8 (dipeptidyl peptidase 8) and 9, partially via interaction of the aminoterminus of NLRP1-CT with the active site of the peptidases [ 117 , 118 ].…”

“…However, the roles of human NLRP1 are only poorly conserved between humans and mice, demonstrating that the NLRP1 is a relatively young evolutionary pathway [ 101 ]. Mechanistically, only human NLRP1 but not murine Nlrp1b is activated by dsRNA, ORF45, UVB, and the ribotoxic stress response [ 102 , 114 , 115 , 125 ]. Talabostat also activates Nlrp1b in murine immune cells; however, this occurs independently of ASC expression and induces mainly pyroptosis with very low levels of secreted IL-1β [ 126 , 127 ].…”