{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:01:11Z","timestamp":1791896471898,"version":"4.3.4"},"reference-count":57,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T00:00:00Z","timestamp":1613692800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:p>Mutations in <jats:italic>OPTN<\/jats:italic> are associated with glaucoma, an eye disease, and also with amyotrophic lateral sclerosis (ALS), a motor neuron disease. A 2\u2010bp insertion in <jats:italic>OPTN<\/jats:italic> (691_692insAG or 2bpIns\u2010OPTN) is associated with both glaucoma and ALS. This mutation results in frame shift after 127 amino acids, giving rise to a protein with C\u2010terminal aberrant sequence. We have explored the mechanism of induction of cell death by this mutant in a motor neuron cell line, NSC\u201034, and also in a retinal cell line, 661W. Compared to wild\u2010type OPTN, this mutant induced more cell death in NSC\u201034 and 661W cells. This mutant localizes predominantly in the nucleus whereas normal OPTN localizes in the cytoplasm. Deletion analysis of 2bpIns\u2010OPTN showed that the aberrant sequence was not essential for cell death induction. This mutant interacts with TANK\u2010binding kinase 1 (Tbk1) but not with OPTN and activates Tbk1. This mutant induced ER stress in NSC\u201034 cells as seen by induction of C\/EBP homologous protein (CHOP) and some other genes. Induction of CHOP, autophagosomal protein LC3\u2010II and cell death by this mutant were abrogated by Tbk1 knockdown and also by 4\u2010phenylbutyric acid, that inhibits ER stress. Induction of CHOP and cell death by 2bpIns\u2010OPTN was autophagy dependent as shown by the effect of Atg5 knockdown. This mutant caused increased formation of LC3\u2010positive aggregates. Treatment of cells with autophagy inducer rapamycin reduced LC3\u2010positive aggregates, CHOP and cell death induced by 2bpIns\u2010OPTN. These results suggest that constitutive activation of Tbk1 by 2bpIns\u2010OPTN leads to impaired autophagy that results in ER stress and cell death.<\/jats:p>","DOI":"10.1111\/febs.15752","type":"journal-article","created":{"date-parts":[[2021,2,6]],"date-time":"2021-02-06T16:59:58Z","timestamp":1612630798000},"page":"4576-4595","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["A glaucoma\u2010 and ALS\u2010associated mutant of OPTN induces neuronal cell death dependent on Tbk1 activity, autophagy and ER stress"],"prefix":"10.1111","volume":"288","author":[{"given":"Swetha","family":"Medchalmi","sequence":"first","affiliation":[{"name":"CSIR\u2010Centre for Cellular and Molecular Biology Hyderabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priyanka","family":"Tare","sequence":"additional","affiliation":[{"name":"CSIR\u2010Centre for Cellular and Molecular Biology Hyderabad 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