Therapeutic potential of PANoptosis: innate sensors, inflammasomes, and RIPKs in PANoptosomes

Abstract

The innate immune system initiates cell death pathways in response to pathogens and cellular stress. Cell death can be either non-lytic (apoptosis) or lytic (PANoptosis, pyroptosis, and necroptosis). PANoptosis has been identified as an inflammatory, lytic cell death pathway driven by caspases and RIPKs that is regulated by PANoptosome complexes, making it distinct from other cell death pathways. Several PANoptosome complexes (including ZBP1-, AIM2-, RIPK1-, and NLRP12-PANoptosomes) have been characterized to date. Furthermore, PANoptosis is implicated in infectious and inflammatory diseases, cancers, and homeostatic perturbations. Therefore, targeting its molecular components offers significant potential for therapeutic development. This review covers PANoptosomes and their assembly, PANoptosome-mediated cell death mechanisms, and ongoing progress in developing therapeutics that target PANoptosis.

Keywords: NLRP12; NLRP3; PANoptosis; PANoptosome; ZBP1; caspase.

Figure 1.. Assembly of different PANoptosome complexes in response to different stimuli.

Diverse pathogenic and sterile cellular insults result in the assembly of various PANoptosome cell death complexes, comprising of innate immune sensors, adaptors, caspases and RIPKs, triggering PANoptosis. During IAV infection, ZBP1 functions as the apical sensor forming the ZBP1-PANoptosome (composed of ZBP1, NLRP3, ASC, caspases-1, −8, and −6, and RIPK3). Similalry, during HSV1 or Francisella infection, pathogens are recognized by the AIM2 sensor resulting in the AIM2-PANoptosome assembly (composed of AIM2, ZBP1, Pyrin, ASC, caspase-1, caspase-8, FADD, RIPK1, and RIPK3). Moreover, Yersinia infection (TAK1 inhibition) followed by LPS priming results in the RIPK1-PANoptosome assembly (composed of RIPK1, NLRP3, ASC, caspase-1, RIPK3, and caspase-8). Furthermore, the NLRP12-PANoptosome (composed of NLRP12, NLRP3, ASC, caspase-1, caspase-8 and RIPK3) is assembled upon Heme+PAMP stimulation. However, the PANoptosome sensors are not yet determined for the TNF + IFN-γ stimulation; the PANoptosome assembly is regulated by JAK/STAT-IRF1-iNOS-NO pathway leading to the assembly of RIPK1, RIPK3, FADD, and caspase-8. The assembly of these PANoptosomes induces the activation of several caspases and RIPKs, which in turn activate executioner molecules like GSDMD, GSDME, and pMLKL resulting in a lytic and inflammatory cell death, i.e. PANoptosis. . The PANoptosome components that were historically classified to be involved in different cell death pathways are represented in different color codes, including blue for pyroptosis, green for apoptosis, and pink for necroptosis. The figure was created using BioRender (https://biorender.com/).