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Structural characterisation of IRE1 activation and substrate recognition by Cryo-EM

Dr MULUKALA NARASIMHA Sandeep

Post Doctoral researcher

UMR Inserm U1242 – OSS – PROSAC Team, RENNES

UMR 5248 CBMN – IECB European Institute of Chemistry and Biology, BORDEAUX

Abstract
The unfolded protein response (UPR) is a conserved signaling network that preserves endoplasmic reticulum (ER) proteostasis under conditions of protein-folding stress. UPR signaling is primarily coordinated by three ER-resident sensors: IRE1α, PERK, and ATF6. Among these, Inositol-Requiring Enzyme 1 alpha (IRE1α) is the most evolutionarily conserved. Upon ER stress, the canonical model suggests that IRE1α detects a proteotoxic imbalance through its luminal domain and undergoes oligomerization. It is suggested that IRE1 oligomerization drives a 2-step structural rearrangement: step 1 involves trans-autophosphorylation of the cytoplasmic-facing kinase domains (face-to-face conformation), followed by step 2, which involves RNase domain activation (back-to-back conformation). The activated RNase domain unconventionally splices the X-box binding protein 1 (XBP1) mRNA, producing the potent transcription factor XBP1s, which promotes adaptive transcriptional programs that restore ER homeostasis. In addition to XBP1 splicing, activated IRE1α can degrade a broader set of ER-associated transcripts through regulated IRE1-dependent decay (RIDD) and, under sustained stress, mediate more promiscuous RNA cleavage (RIDDLE), expanding its impact from adaptive, pro-survival signaling to pro-death signaling.
Despite extensive biochemical and structural studies, the molecular basis of IRE1α activation remains elusive and highly debated. Competing models propose that either direct binding of misfolded proteins or dissociation of the ER chaperone BiP acts as the primary trigger. Further, it remains unclear how the severity of activation is linked to RNase substrate selectivity, including how IRE1α discriminates between canonical XBP1 splicing and alternative RNA decay programs such as RIDD and related noncanonical cleavage activities. Together, these questions highlight the critical gap in our understanding of how luminal domain sensing is coupled to cytoplasmic RNase activation and selective mRNA processing. To answer these specific questions, our study aims to define the structural determinants of IRE1α activation by determining high-resolution structures of full-length IRE1α and its cytoplasmic kinase–RNase module in complex with XBP1 mRNA. Elucidating these assemblies will clarify the mechanisms of stress sensing and substrate engagement, providing a crucial framework for targeting IRE1α signaling in diseases associated with chronic ER stress, including cancer and neurodegeneration.

Source : OpenAgenda

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