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Identification of a splice variant of optineurin which is defective in autophagy and phosphorylation.
Moharir, Shivranjani C; Bansal, Megha; Ramachandran, Gopalakrishna; Ramaswamy, Rajashree; Rawat, Shivali; Raychaudhuri, Swasti; Swarup, Ghanshyam.
Afiliación
  • Moharir SC; CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, India.
  • Bansal M; CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, India.
  • Ramachandran G; CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, India.
  • Ramaswamy R; CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, India.
  • Rawat S; CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, India.
  • Raychaudhuri S; CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, India.
  • Swarup G; CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, India. Electronic address: gshyam@ccmb.res.in.
Biochim Biophys Acta Mol Cell Res ; 1865(11 Pt A): 1526-1538, 2018 11.
Article en En | MEDLINE | ID: mdl-30327196
Optineurin (Optn) is an autophagy receptor that performs various functions in cargo-selective and non-selective autophagy. Here, we have identified and characterized a splice variant of mouse optineurin mRNA, which produces a truncated protein lacking N-terminal 157 amino acids (d157mOptn). This mRNA and protein are expressed in several tissues and cells. d157mOptn has an intact LC3-interacting region and a serine (S187) in it. However, unlike normal optineurin, the d157mOptn was not phosphorylated at this site when expressed in mammalian cells, and showed reduced interaction with TBK1 (tank binding kinase) that mediates phosphorylation at S187 (S177 in human OPTN). This phosphorylation of Optn required intact N-terminal sequence as well as functional C-terminal ubiquitin-binding domain. Unlike normal optineurin, d157mOptn was unable to promote autophagosome and autolysosome formation upon expression in Optn-deficient cells. d157mOptn was recruited to mutant huntingtin aggregates, but unlike wild type optineurin, it was unable to clear these aggregates by autophagy in neuronal NSC-34 cells. Phospho-TBK1 was seen around mutant Huntingtin aggregates in Optn overexpressing cells but it was reduced in cells overexpressing d157mOptn. Thus, we have identified an isoform of mouse optineurin which is defective in cargo-selective and non-selective autophagy possibly due to loss of phosphorylation and impaired interaction with TBK1. This isoform, which inhibits autophagosome formation in neuronal cells, might be involved in selectively modulating some of the functions of Optn, such as autophagy. Our results provide an insight into the role of N-terminal domain of Optn in various autophagic functions.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Autofagia / Empalme del ARN / Factor de Transcripción TFIIIA Tipo de estudio: Diagnostic_studies / Prognostic_studies Idioma: En Revista: Biochim Biophys Acta Mol Cell Res Año: 2018 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Autofagia / Empalme del ARN / Factor de Transcripción TFIIIA Tipo de estudio: Diagnostic_studies / Prognostic_studies Idioma: En Revista: Biochim Biophys Acta Mol Cell Res Año: 2018 Tipo del documento: Article