Polyubiquitin Binding to Optineurin Is Required for Optimal Activation of TANK-binding Kinase 1 and Production of Interferon β

Abstract

Background:Optineurin is a polyubiquitin-binding protein of unknown function. Result: Macrophages from mice expressing a polyubiquitin-binding defective mutant of optineurin show reduced activation of TANK-binding kinase 1 (TBK1) and reduced production of interferon ␤. Conclusion:The binding of polyubiquitin to optineurin is required for optimal activation and function of TBK1. Significance: This study identifies a new physiological role for optineurin.

Toward an integrative view of Optineurin functions

“…24,80 The ubiquitin-binding function of Optn is also important for antiviral immune response, selective autophagy of cytosolic bacteria and Transferrin receptor (TfR) recycling. 43,55,78 However, the role of Ub-binding activity in some Optn-mediated functions, such as the transport of lysosomal proteins, remains to be determined. Since ubiquitination of NEMO was shown to be important for NFκB activation, ubiquitination of Optn may also be important for its subcellular localization and functions.…”

“…For example, Optn is phosphorylated on the same residue (Ser177) by both TBK1 and Plk1, but with different consequences on the subcellular localization and function of Optn. 43,55,60 It will be thus of importance to generate Optn forms carrying mutations in the consensus phosphorylation motif of each kinase and to test their effects on Optn functions. Analysis of such mutants will help to define the link between autophagy and mitosis and to answer whether Optn-mediated autophagy is antagonized by phosphorylation of Optn by Plk1 during mitosis.…”

“…42 mice] suggested that Optn may rather act as an activator of TBK1 kinase activity through its interaction with ubiquitinated targets in response to lipopolysaccharide (LPS) or poly(I:C). 43 Optn is phosphorylated on residues Ser177 and Ser513 by TBK1 and IKKβ, respectively, and Optn S177 phosphorylation was reduced in LPS-stimulated bone marrow-derived macrophages from Optn (D477N/D477N) mice ( Table 2). More recently, it has been shown that the Q398X and E478G mutations of Optn that have been associated with amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder (see below), have lost their capacity to inhibit IRF3 activation in response to MDA5 or TRIF overexpression.…”

“…Such a link is also emphasized by the observation that functions of Optn in antiviral immunity and defense against bacteria are both dependent on the ability of Optn to interact with polyubiquitinated substrates. 42,43,55 Optn as a regulator of mitosis. Polo-like kinase 1 (Plk1) is a key regulator of cell division in eukaryotic cells.…”

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

“…The interaction between TBK1 and OPTN1 is a key factor in autophagy and inflammation (Maruyama et al, 2010;Maruyama and Kawakami, 2013;Thomas et al, 2013;Kachaner et al, 2012). TBK1 enhances the autophagic turnover of bacteria-bound ubiquitylated proteins (Wild et al, 2011;Gleason et al, 2011), through the phosphorylation of OPTN and SQSTM1 (Morton et al, 2008;Pilli et al, 2012) and promoting the interaction of OPTN with LC3. TBK1 co-localization with OPTN and SQSTM1 within autophagosomes, even in cells carrying SOD1, TARDBP and FUS mutation, suggests a still undisclosed role of these proteins in aggregate formation in ALS (Keller et al, 2012).…”