Ribosome-rescuer PELO catalyzes the oligomeric assembly of NOD-like receptor family proteins via activating their ATPase enzymatic activity

• Published in: Immunity (Cambridge, Mass.) Vol. 56; no. 5; pp. 926 - 943.e7
• Main Authors: Wu, Xiurong, Yang, Zhang-Hua, Wu, Jianfeng, Han, Jiahuai
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.05.2023
• Subjects: Adenosine Triphosphatases - metabolism; Apoptosis Regulatory Proteins - metabolism; ATPase; Calcium-Binding Proteins - chemistry; Calcium-Binding Proteins - metabolism; catalyzer; Flagellin - metabolism; inflammasome; Inflammasomes - metabolism; Neuronal Apoptosis-Inhibitory Protein - chemistry; Neuronal Apoptosis-Inhibitory Protein - metabolism; NLR Proteins - metabolism; NLRC4; NLRP3; NLRs; oligomerization; PELO; catalyzer; oligomerization; inflammasome; ATPase; NLRP3; NLRs; NLRC4; PELO
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2023.02.014

NOD-like receptors (NLRs) are pattern recognition receptors for diverse innate immune responses. Self-oligomerization after engagement with a ligand is a generally accepted model for the activation of each NLR. We report here that a catalyzer was required for NLR self-oligomerization. PELO, a well-known surveillance factor in translational quality control and/or ribosome rescue, interacted with all cytosolic NLRs and activated their ATPase activity. In the case of flagellin-initiated NLRC4 inflammasome activation, flagellin-bound NAIP5 recruited the first NLRC4 and then PELO was required for correctly assembling the rest of NLRC4s into the NLRC4 complex, one by one, by activating the NLRC4 ATPase activity. Stoichiometric and functional data revealed that PELO was not a structural constituent of the NLRC4 inflammasome but a powerful catalyzer for its assembly. The catalytic role of PELO in the activation of cytosolic NLRs provides insight into NLR activation and provides a direction for future studies of NLR family members. [Display omitted] •PELO interacts with all cytosolic NLRs and potentiates their ATPase activity•Activation of the ATPase by PELO is required for the oligomeric assembly of NLRs•PELO controls the activation of NLRs, including NLRP3 and NLRC4•PELO’s function in NLR activation is independent of its function in ribosome rescue The ATPase activity of NLRs is essential for driving their oligomeric assembly and activation, yet it is poorly understood. Wu et al. reveal that the ribosome-rescuer PELO catalyzes self-oligomerization of all cytosolic NLRs via potentiating their ATPase activity, thus controlling both inflammasomal and non-inflammasomal NLR activation.