Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Aug;288(15):4576-4595.
doi: 10.1111/febs.15752. Epub 2021 Feb 19.

A glaucoma- and ALS-associated mutant of OPTN induces neuronal cell death dependent on Tbk1 activity, autophagy and ER stress

Swetha Medchalmi  1 , Priyanka Tare  1 , Zuberwasim Sayyad  1 , Ghanshyam Swarup  1
Affiliations
Free article

A glaucoma- and ALS-associated mutant of OPTN induces neuronal cell death dependent on Tbk1 activity, autophagy and ER stress

Swetha Medchalmi et al. FEBS J. 2021 Aug.
Free article

Abstract

Mutations in OPTN are associated with glaucoma, an eye disease, and also with amyotrophic lateral sclerosis (ALS), a motor neuron disease. A 2-bp insertion in OPTN (691_692insAG or 2bpIns-OPTN) is associated with both glaucoma and ALS. This mutation results in frame shift after 127 amino acids, giving rise to a protein with C-terminal aberrant sequence. We have explored the mechanism of induction of cell death by this mutant in a motor neuron cell line, NSC-34, and also in a retinal cell line, 661W. Compared to wild-type OPTN, this mutant induced more cell death in NSC-34 and 661W cells. This mutant localizes predominantly in the nucleus whereas normal OPTN localizes in the cytoplasm. Deletion analysis of 2bpIns-OPTN showed that the aberrant sequence was not essential for cell death induction. This mutant interacts with TANK-binding kinase 1 (Tbk1) but not with OPTN and activates Tbk1. This mutant induced ER stress in NSC-34 cells as seen by induction of C/EBP homologous protein (CHOP) and some other genes. Induction of CHOP, autophagosomal protein LC3-II and cell death by this mutant were abrogated by Tbk1 knockdown and also by 4-phenylbutyric acid, that inhibits ER stress. Induction of CHOP and cell death by 2bpIns-OPTN was autophagy dependent as shown by the effect of Atg5 knockdown. This mutant caused increased formation of LC3-positive aggregates. Treatment of cells with autophagy inducer rapamycin reduced LC3-positive aggregates, CHOP and cell death induced by 2bpIns-OPTN. These results suggest that constitutive activation of Tbk1 by 2bpIns-OPTN leads to impaired autophagy that results in ER stress and cell death.

Keywords: ER stress; Tbk1; amyotrophic lateral sclerosis; glaucoma; optineurin.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Kachaner D, Genin P, Laplantine E & Weil R (2012) Toward an integrative view of Optineurin functions. Cell Cycle 11, 2808-2818.
    1. Ying H & Yue BY (2012) Cellular and molecular biology of optineurin. Int Rev Cell Mol Biol 294, 223-258.
    1. Minegishi Y, Nakayama M, Iejima D, Kawase K & Iwata T (2016) Significance of optineurin mutations in glaucoma and other diseases. Prog Retinal Eye Res 55, 149-181.
    1. Markovinovic A, Cimbro R, Ljutic T, Kriz J, Rogelj B & Munitic I (2017) Optineurin in amyotrophic lateral sclerosis: multifunctional adaptor protein at the crossroads of different neuroprotective mechanisms. Prog Neurogibol 154, 1-20.
    1. Toth RP & Atkin JD (2018) Dysfunction of optineurin in amyotrophic lateral sclerosis and glaucoma. Front Immunol 9, 1017.

Publication types

MeSH terms

LinkOut - more resources