The PANoptosome: A Deadly Protein Complex Driving Pyroptosis, Apoptosis, and Necroptosis (PANoptosis)

Abstract

Programmed cell death is regulated by evolutionarily conserved pathways that play critical roles in development and the immune response. A newly recognized pathway for proinflammatory programmed cell death called PANoptosis is controlled by a recently identified cytoplasmic multimeric protein complex named the PANoptosome. The PANoptosome can engage, in parallel, three key modes of programmed cell death-pyroptosis, apoptosis, and necroptosis. The PANoptosome components have been implicated in a wide array of human diseases including autoinflammatory diseases, neurodegenerative diseases, cancer, microbial infections, and metabolic diseases. Here, we review putative components of the PANoptosome and present a phylogenetic analysis of their molecular domains and interaction motifs that support complex assembly. We also discuss genetic data that suggest PANoptosis is coordinated by scaffolding and catalytic functions of the complex components and propose mechanistic models for PANoptosome assembly. Overall, this review presents potential mechanisms governing PANoptosis based on evolutionary analysis of the PANoptosome components.

Keywords: ASC; PANoptosis; PANoptosome; RIPK1; RIPK3; ZBP1; caspase-1; caspase-8.

Figure 1

The molecular components of the PANoptosome and the human health significance of PANoptosis. (A) Proposed domains of PANoptosome components required for complex assembly in response to various stimuli. PANoptosome assembly is mediated by key molecular motifs collectively called death fold domains. Genetic evidence suggests that PANoptosome activation is inhibited by TAK1, PSTPIP2, SHARPIN, HOIP, HOIL-1, and A20. (B) Defects in the PANoptosome components have been implicated in a range of human diseases.

Figure 2

The distribution of molecular motifs present in PANoptosome components. (A) Distribution of assembly domains. (B) Distribution of catalytic domains. (C) Distribution of sensing domains. All domain names and their distributions were obtained from the Pfam database (Sonnhammer et al., 1997). Sunburst visualizations and color assignment legends were exported from the Pfam database.

Figure 3

Using phylogenetic analysis to understand the molecular mechanism governing PANoptosome assembly. Phylogenetic analysis of assembly domains present in PANoptosome components. Amino acid sequences corresponding to the domains were obtained from the Uniprot database (The UniProt Consortium, 2015). Multiple sequence alignment and phylogenetic analysis were performed using the Mega-X software package (Kumar et al., 2018). ClustalW was used for multiple sequence alignment. Maximum likelihood analysis with bootstrap 500 iterations was used to generate the phylogenetic tree. The consensus phylogenetic tree is shown. If a protein contains multiple copies of a domain, the domains are numbered beginning at the N-terminus. For example, the first occurrence of the RHIM domain in ZBP1 is named RHIM 1, and the second occurrence is named RHIM 2.