Frontiers in Immunology (Jun 2018)
Altered Functions and Interactions of Glaucoma-Associated Mutants of Optineurin
Abstract
Optineurin (OPTN) is an adaptor protein that is involved in mediating a variety of cellular processes such as signaling, vesicle trafficking, and autophagy. Certain mutations in OPTN (gene OPTN) are associated with primary open angle glaucoma, a leading cause of irreversible blindness, and amyotrophic lateral sclerosis, a fatal motor neuron disease. Glaucoma-associated mutations of OPTN are mostly missense mutations. OPTN mediates its functions by interacting with various proteins and altered interactions of OPTN mutants with various proteins primarily contribute to functional defects. It interacts with Rab8, myosin VI, Huntigtin, TBC1D17, and transferrin receptor to mediate various membrane vesicle trafficking pathways. It is an autophagy receptor that mediates cargo-selective as well as non-selective autophagy. Glaucoma-associated mutants of OPTN, E50K, and M98K, cause defective vesicle trafficking, autophagy, and signaling that contribute to death of retinal ganglion cells (RGCs). Transgenic mice expressing E50K-OPTN show loss of RGCs and persistent reactive gliosis. TBK1 protein kinase, which mediates E50K-OPTN and M98K-OPTN induced cell death, is emerging as a potential drug target. Autoimmunity has been implicated in glaucoma but involvement of OPTN or its mutants in autoimmnity has not been explored. In this review, we highlight the main functions of OPTN and how glaucoma-associated mutants alter these functions. We also discuss some of the controversies, such as the role of OPTN in signaling to transcription factor NF-κB, interferon signaling, and use of RGC-5 cell line as a cell culture model.
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