Optineurin is a multidomain adaptor protein that integrates ubiquitin signalling, kinase regulation, and autophagy to coordinate innate immune defences and cellular homeostasis. Initially identified as a tumour necrosis factor-α (TNF-α)-inducible coiled-coil protein related to the NEMO protein, namely FIP-2, optineurin participates in pathogen restriction through selective autophagy and Parkin-mediated mitophagy. In these processes, TBK1-driven phosphorylation enhances optineurin LC3 binding and cargo capture. Dysregulation of optineurin is implicated in several diseases, such as glaucoma, amyotrophic lateral sclerosis (ALS), frontotemporal degeneration (FTD), inflammatory bowel disease, and multiple cancers. Mechanistically, disease links arise from defects in ubiquitin recognition (UBAN domain), impaired TBK1–optineurin coupling, altered autophagic flux, and imbalanced inflammatory signalling. Additionally, optineurin plays a role in restraining necroptosis via RIPK1 and limiting apoptosis through interactions with caspase-8, the dysregulation of which may further contribute to pathogenesis. These findings establish optineurin as a context-specific homeostatic regulator that connects organelle quality control and innate immunity. Key challenges include disentangling optineurin’s pleiotropic interactions and developing modality-specific interventions that avoid on-target toxicity, suggesting that future work using single-cell profiling, precise genome editing, and super-resolution imaging of living cells will improve the mechanism map and make biomarker-guided mutation-aware therapy targeting the optineurin–TBK1 ubiquitin axis possible.
Zhang et al. (Fri,) studied this question.