Higher-order assemblies in immune signaling: supramolecular complexes and phase separation

Protein Cell. 2021 Sep;12(9):680-694. doi: 10.1007/s13238-021-00839-6. Epub 2021 Apr 9.

Abstract

Signaling pathways in innate and adaptive immunity play vital roles in pathogen recognition and the functions of immune cells. Higher-order assemblies have recently emerged as a central principle that governs immune signaling and, by extension, cellular communication in general. There are mainly two types of higher-order assemblies: 1) ordered, solid-like large supramolecular complexes formed by stable and rigid protein-protein interactions, and 2) liquid-like phase-separated condensates formed by weaker and more dynamic intermolecular interactions. This review covers key examples of both types of higher-order assemblies in major immune pathways. By placing emphasis on the molecular structures of the examples provided, we discuss how their structural organization enables elegant mechanisms of signaling regulation.

Keywords: BCR; RLR; TCR; TLR; TNFR; cGAS; death domain; higher-order assembly, phase separation, signalosome; immune signaling; inflammasome.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptive Immunity
  • Animals
  • DEAD Box Protein 58 / genetics
  • DEAD Box Protein 58 / immunology
  • DEAD Box Protein 58 / metabolism
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / immunology
  • DEAD-box RNA Helicases / metabolism
  • Gene Expression Regulation
  • Humans
  • Immunity, Innate*
  • Inflammasomes / genetics
  • Inflammasomes / immunology*
  • Inflammasomes / ultrastructure
  • Models, Molecular
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / immunology*
  • Multiprotein Complexes / metabolism
  • Protein Conformation
  • Protein Interaction Mapping
  • Receptors, Antigen, B-Cell / genetics
  • Receptors, Antigen, B-Cell / immunology*
  • Receptors, Antigen, B-Cell / metabolism
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / immunology
  • Receptors, Immunologic / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / immunology
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Signal Transduction / immunology*
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / immunology
  • Toll-Like Receptors / metabolism

Substances

  • Inflammasomes
  • Multiprotein Complexes
  • Receptors, Antigen, B-Cell
  • Receptors, Antigen, T-Cell
  • Receptors, Immunologic
  • Receptors, Tumor Necrosis Factor, Type I
  • TNFRSF1A protein, human
  • Toll-Like Receptors
  • RIGI protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases