Autophagy-independent cytoprotection by optineurin from toxicity of aggregates formed by mutant huntingtin and mutant ataxin-3.

An important feature of several neurodegenerative diseases is the formation of pathological structures containing aggregated proteins. The autophagy receptor optineurin/OPTN is frequently observed in these structures. The role played by optineurin in these aggregates is not clear. In this study, we explored whether optineurin has a cytoprotective role in the cells having mutant protein aggregates. We overexpressed mutant huntingtin having 97 glutamine repeats (mHtt) and mutant ataxin-3 having 130 glutamine repeats (mAtax-3) in wild-type and optineurin-deficient neuronal (N2A) and non-neuronal cells (Optn-/- mouse embryonic fibroblasts) and determined the percentage of dead cells with mutant protein aggregates. Optineurin-deficient cells having mHtt or mAtax-3 aggregates showed higher cell death as compared to wild-type cells having mutant protein aggregates. Confocal microscopy revealed that optineurin formed a shell around mHtt and mAtax-3 aggregates through its C-terminal domain. The C-terminal domain of optineurin, which lacks LC3-interacting region required for autophagy, was necessary and sufficient to reduce cytotoxicity of mHtt and mAtax-3 aggregates. Our results show that in the absence of optineurin, mutant protein aggregates are highly toxic, revealing an autophagy-independent cytoprotective function of optineurin, which is mediated by its C-terminal domain.
(© The Author(s) 2022. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)