PANoptosome signaling and therapeutic implications in infection: central role for ZBP1 to activate the inflammasome and PANoptosis

The innate immune response provides the first line of defense against infection and disease. Regulated cell death (RCD) is a key component of innate immune activation, and RCD must be tightly controlled to clear pathogens while preventing excess inflammation. Recent studies have highlighted a central role for the innate immune sensor Z-DNA-binding protein 1 (ZBP1) as an activator of a form of inflammatory RCD called PANoptosis, which is regulated by a multifaceted cell death complex called the PANoptosome. In response to influenza A virus infection, ZBP1 activates the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, which then acts as an integral component of the ZBP1-PANoptosome to drive inflammatory cell death, PANoptosis. In this context, the NLRP3 inflammasome is critical for caspase-1 activation and proinflammatory cytokine interleukin (IL)-1β and IL-18 maturation, but dispensable for cell death due to functional redundancies between PANoptosome molecules. Similarly, ZBP1 is also central to the absent in melanoma 2 (AIM2)-PANoptosome; this PANoptosome forms in response to Francisella novicida and herpes simplex virus 1 infection and incorporates the AIM2 inflammasome as an integral component. In this review, we will discuss the critical roles of ZBP1 in mediating innate immune responses through inflammasomes, PANoptosomes, and PANoptosis during infection. An improved understanding of the molecular mechanisms of innate immunity and cell death will be essential for the development of targeted modalities that can improve patient outcomes by mitigating severe disease.