Mechanism of NAIP-NLRC4 inflammasome activation revealed by cryo-EM structure of unliganded NAIP5.

The nucleotide-binding domain (NBD), leucine rich repeat (LRR) domain containing protein family (NLR family) apoptosis inhibitory proteins (NAIPs) are cytosolic receptors that play critical roles in the host defense against bacterial infection. NAIPs interact with conserved bacterial ligands and activate the NLR family caspase recruitment domain containing protein 4 (NLRC4) to initiate the NAIP-NLRC4 inflammasome pathway. Here we found the process of NAIP activation is completely different from NLRC4. Our cryo-EM structure of unliganded mouse NAIP5 adopts an unprecedented wide-open conformation, with the nucleating surface fully exposed and accessible to recruit inactive NLRC4. Upon ligand binding, the winged helix domain (WHD) of NAIP5 undergoes roughly 20° rotation to form a steric clash with the inactive NLRC4, which triggers the conformational change of NLRC4 from inactive to active state. We also show the rotation of WHD places the 17-18 loop at a position that directly bind the active NLRC4 and stabilize the NAIP5-NLRC4 complex. Overall, these data provide structural mechanisms of inactive NAIP5, the process of NAIP5 activation and NAIP-dependent NLRC4 activation.

Structural mechanisms of inflammasome regulation revealed by cryo-EM studies.

Inflammasomes are cytosolic protein complexes that form in response to pathogen or damage signals and initiate inflammation. Signal transduction in the inflammasome pathway occurs via protein-protein interaction, protein conformational change, and oligomerization. Recent advances in structural biology have provided multiple insights in inflammasome regulation that are both biologically intriguing and therapeutically valuable. In this review, we summarize the current understanding of three most studied inflammasome complexes: the NAIP/NLRC4, NLRP1, and NLRP3 inflammasomes. We discuss the general mechanisms and unique features of their regulation and how investigating these systems may contribute to therapeutic applications.

Structural aspects of the MHC expression control system.

The major histocompatibility complex (MHC) spans innate and adaptive immunity by presenting antigenic peptides to CD4+ and CD8+ T cells. Multiple transcription factors form an enhanceosome complex on the MHC promoter and recruit transcriptional machinery to activate gene transcription. Immune signals such as interferon-γ (IFN-γ) control MHC level by up-regulating components of the enhanceosome complex. As MHC plays crucial roles in immune regulation, alterations in the MHC enhanceosome structure will alter the pace of rapid immune responses at the transcription level and lead to various diseases related to the immune system. In this review, we discuss the current understanding of the MHC enhanceosome, with a focus on the structures of MHC enhanceosome components and the molecular basis of MHC enhanceosome assembly.