OPTN

Optineurin (OPTN) is a ubiquitously expressed, predominantly cytoplasmic coiled-coil adaptor protein that functions as a selective autophagy receptor. It carries two functional cargo-recognition modules: an LC3-interacting region (LIR motif, residues 176-181, with the critical Phe178) that binds ATG8-family modifiers (MAP1LC3A/B, GABARAP, GABARAPL1, GABARAPL2), and a UBAN (ubiquitin binding in ABIN and NEMO) motif (residues 474-479, with the essential Asp474/Phe475) that binds linear (M1) and K63-linked polyubiquitin chains. By simultaneously engaging ubiquitinated cargo and ATG8 proteins on the nascent autophagosomal membrane, OPTN bridges cargo to the autophagy machinery. Its C-terminus contains a CCHC NOA-type zinc finger (residues 547-577) that coordinates Zn2+. OPTN partners with and is activated by the kinase TBK1, which phosphorylates OPTN at Ser177 adjacent to the LIR, markedly increasing LC3 binding affinity and thereby driving cargo-selective autophagy. Through this mechanism OPTN mediates antibacterial xenophagy of ubiquitin-coated cytosolic bacteria (e.g. Salmonella) and PINK1/Parkin-dependent mitophagy of damaged mitochondria, acting alongside the related receptors SQSTM1/p62 and CALCOCO2/NDP52. As a NEMO-related protein, OPTN also regulates innate immune and inflammatory signaling: it negatively regulates canonical NF-kB signaling (competing for polyubiquitin within the TNFR1 complex) and dampens virus-triggered IFN-beta induction, while recruiting and activating TBK1 at the Golgi after RNA-virus sensing. Independently, OPTN links myosin VI and GTP-Rab8 to the Golgi complex, contributing to Golgi ribbon organization, post-Golgi exocytosis, and Rab8/TBC1D17-dependent endocytic recycling (e.g. of the transferrin receptor). OPTN mutations cause primary open-angle glaucoma (GLC1E; e.g. E50K), normal-pressure glaucoma, and amyotrophic lateral sclerosis with or without frontotemporal dementia (ALS12; e.g. the UBAN mutant E478G and the truncation Q398X), linking impaired selective autophagy and vesicular trafficking to neurodegeneration.

Disorders

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• disabled_macroautophagy via Amyotrophic Lateral Sclerosis