Gigaxonin is required for intermediate filament transport

Author:

Renganathan Bhuvanasundar1ORCID,Zewe James P.2,Cheng Yuan3,Paumier Jean‐Michel2,Kittisopikul Mark1,Ridge Karen M.3,Opal Puneet2,Gelfand Vladimir I.1ORCID

Affiliation:

1. Department of Cell and Developmental Biology Feinberg School of Medicine, Northwestern University Chicago Illinois USA

2. Ken and Ruth Davee Department of Neurology Feinberg School of Medicine, Northwestern University Chicago Illinois USA

3. Division of Pulmonary and Critical Care Medicine Department of Medicine Northwestern University, Feinberg School of Medicine Chicago Illinois USA

Abstract

AbstractGigaxonin 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.

Funder

National Institute of General Medical Sciences

National Institute of Neurological Disorders and Stroke

Publisher

Wiley

Subject

Genetics,Molecular Biology,Biochemistry,Biotechnology

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