Gigaxonin is required for intermediate filament transport.
FASEB J
; 37(5): e22886, 2023 05.
Article
in En
| MEDLINE
| ID: mdl-37043392
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cytoskeletal Proteins
/
Giant Axonal Neuropathy
Limits:
Humans
Language:
En
Journal:
FASEB J
Journal subject:
BIOLOGIA
/
FISIOLOGIA
Year:
2023
Type:
Article
Affiliation country:
United States