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

Shiyu Xia,Chen Shen,Tian-Min Fu,Zhenhang Chen

doi:10.1007/s13238-021-00839-6

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.

Highlights

The immune system is typically categorized into innate immunity and adaptive immunity
Recent studies have revealed that higher-order assembly, by which biomolecules cluster into large structures of defined or irregular shapes, provides a common theme in innate and adaptive immunity, and elegant mechanisms of sensitivity control and signal transduction (Yin et al, 2015; Du and Chen, 2018; Courtney et al, 2018)
The death domain (DD) superfamily comprises four subfamilies known as DD, death effector domain (DED), Higher-order assemblies in immune signaling caspase recruitment domain (CARD), and Pyrin domain (PYD) (Park et al, 2007a)

Summary

INTRODUCTION

The immune system is typically categorized into innate immunity and adaptive immunity. The DD superfamily comprises four subfamilies known as DD, death effector domain (DED), Higher-order assemblies in immune signaling caspase recruitment domain (CARD), and Pyrin domain (PYD) (Park et al, 2007a) Despite divergence in their primary sequence, the families share a conserved six-helix bundle structure, with minor variations in the lengths and orientations of the helices. Different from the ASC-dependent inflammasomes, the helical assembly of the NLRC4 inflammasome is initiated through the activation of the sensor and nucleator NAIP by bacterial ligands (Diebolder et al, 2015; Zhang et al, 2015) In this spiral structure, NLRC4 CARD forms a filament at the center of the spiral, whereas the NACHT and LRR domains assemble into disk-like structures along the CARD filament axis (Fig. 4C). Other known inhibitors of DD assembly include PYD-only proteins ASC2 and POP2, albeit unclear molecular mechanisms (Natarajan et al, 2006; Ratsimandresy et al, 2017)

A TNFR PATHWAY

CONCLUDING REMARKS

ETHICS APPROVAL