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.

Keywords: CYLD; NF-κB; Rab8; TBK1; autophagy; glaucoma; optineurin; vesicle trafficking.

Figure 1

Disease-associated mutations, interactions, and cellular functions of optineurin. (A) Various domains and disease-associated mutants of OPTN are shown. Abbreviations: CC, coiled coil; LZ, leucine zipper; LIR, LC3 interacting region; UBD, ubiquitin-binding domain; ZF, zinc finger. (B) OPTN-interacting proteins and their binding sites on OPTN are shown. (C) Interacting partners of OPTN involved in various cellular functions are depicted.

Figure 2

661W is a retinal ganglion precursor-like cell line that shows features of both retinal ganglion and cone photoreceptor cells. These cells are probably derived from either retinal precursor cells (which give rise to various types of cells in the retina) or retinal ganglion progenitor cells, which differentiate into retinal ganglion cells.

Figure 3

E50K-optineurin induces death of retinal cells by various mechanisms that may contribute to glaucoma pathogenesis.

Figure 4

Optineurin (OPTN) acts as a molecular switch that maintains a balance between transferrin receptor (TFRC) recycling and autophagy in retinal cells. M98K mutation in OPTN alters this balance leading to enhanced autophagy that in turn results in reduced recycling of TFRC. Enhanced phosphorylation of M98K-OPTN by TBK1 at S177 plays a crucial role in autophagy-dependent degradation of TFRC leading to cell death.