Gigaxonin is required for intermediate filament transport.

Autor: Renganathan B; Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Zewe JP; Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Cheng Y; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA., Paumier JM; Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Kittisopikul M; Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Ridge KM; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA., Opal P; Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Gelfand VI; Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2023 May; Vol. 37 (5), pp. e22886.
DOI: 10.1096/fj.202202119R
Abstrakt: Gigaxonin is an adaptor protein for E3 ubiquitin ligase substrates. It is necessary for ubiquitination and degradation of intermediate filament (IF) proteins. Giant axonal neuropathy is a pathological condition caused by mutations in the GAN gene that encodes gigaxonin. This condition is characterized by abnormal accumulation of IFs in both neuronal and non-neuronal cells; however, it is unclear what causes IF aggregation. In this work, we studied the dynamics of IFs using their subunits tagged with a photoconvertible protein mEOS 3.2. We have demonstrated that the loss of gigaxonin dramatically inhibited transport of IFs along microtubules by the microtubule motor kinesin-1. This inhibition was specific for IFs, as other kinesin-1 cargoes, with the exception of mitochondria, were transported normally. Abnormal distribution of IFs in the cytoplasm can be rescued by direct binding of kinesin-1 to IFs, demonstrating that transport inhibition is the primary cause for the abnormal IF distribution. Another effect of gigaxonin loss was a more than 20-fold increase in the amount of soluble vimentin oligomers in the cytosol of gigaxonin knock-out cells. We speculate that these oligomers saturate a yet unidentified adapter that is required for kinesin-1 binding to IFs, which might inhibit IF transport along microtubules causing their abnormal accumulation.
(© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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