Porcine Deltacoronavirus M Protein Binds NLRP3 to Promote Inflammasome Assembly via Competition with TRIM31

ABSTRACT

Porcine deltacoronavirus (PDCoV) infection induces severe intestinal inflammation and acute diarrhea in piglets, resulting substantial economic losses. The NLR family pyrin domain containing 3 (NLRP3) inflammasome, a key component of the innate immune system, drives interleukin (IL)‐1β maturation, and its excessive activation is closely linked to viral pathogenesis. However, its role in PDCoV infection remains unclear. Here, we report that PDCoV infection induces IL‐1β maturation through NLRP3 inflammasome activation both in vivo and in vitro , and the M protein promotes NLRP3 inflammasome assembly and activation. Mechanistically, M protein directly bound the LRR domain of the NLRP3 protein. Seven residues (M116, H201, T205, K207, R212, Y214, and M217) in the β‐sheet core of the M protein formed hydrogen bonds with eight residues (Y861, R920, E949, E1007, Y1009, K1015, N1011, and E1033) in the α‐helix groove of the LRR domain, serving as critical determinants of binding. Moreover, the M protein protects NLRP3 from proteasomal degradation by removing tripartite motif‐containing 31‐mediated K48‐linked polyubiquitin chains on NLRP3, thereby stabilizing NLRP3 protein. Collectively, these findings reveal a novel mechanism of NLRP3 inflammasome activation during PDCoV infection, offering valuable insights into PDCoV pathogenesis that may facilitate the design of antiviral agents against PDCoV.