Kazrin promotes dynein/dynactin-dependent traffic from early to recycling endosomes
- Instituto de Biología Molecular de Barcelona, Spain
Abstract
Kazrin is a protein widely expressed in vertebrates whose depletion causes a myriad of developmental defects, in part derived from altered cell adhesion and migration, as well as failure to undergo Epidermal to Mesenchymal Transition. However, the primary molecular role of kazrin, which might contribute to all these functions, has not been elucidated yet. We previously identified one of its isoforms, kazrin C, as a protein that potently inhibits clathrin-mediated endocytosis when overexpressed. We now generated kazrin knock out mouse embryonic fibroblasts to investigate its endocytic function. We found that kazrin depletion delays juxtanuclear enrichment of internalized material, indicating a role in endocytic traffic from early to recycling endosomes. Consistently, we found that the C-terminal domain of kazrin C, predicted to be an intrinsically disordered region, directly interacts with several early endosome (EE) components, and that kazrin depletion impairs retrograde motility of these organelles. Further, we noticed that the N-terminus of kazrin C shares homology with dynein/dynactin adaptors and that it directly interacts with the dynactin complex and the dynein light intermediate chain 1. Altogether, the data indicate that one of the primary kazrin functions is to facilitate endocytic recycling by promoting dynein/dynactin-dependent transport of EEs or EE-derived transport intermediates to the recycling endosomes.
Data availability
All data presented or analyzed in the manuscript has been loaded in Dryad DOI https://doi.org/10.5061/dryad.k6djh9w9q
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Data from: Kazrin promotes dynein/dynactin-dependent traffic from early to recycling endosomesDryad Digital Repository, doi:10.5061/dryad.k6djh9w9q.
Article and author information
Author details
Funding
Agencia Estatal de Investigación (BFU2017-82959-P)
- María Isabel Geli
Agencia Estatal de Investigación (PID2020-120053GB-I00)
- María Isabel Geli
Ministerio de Ciencia, Innovación y Universidades (EQC2018-004541 EU FeDer)
- Elena Rebollo
Consejo Superior de Investigaciones Científicas (CSIC1501/18)
- Elena Rebollo
Ministerio de Ciencia, Innovación y Universidades (BES-2015-071691)
- Ines Hernandez-Perez
Ministerio de Ciencia, Innovación y Universidades (BES-2015-071691)
- Adrian Baumann
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Hernandez-Perez et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Kazrin promotes dynein/dynactin-dependent traffic from early to recycling endosomes
eLife 12:e83793.
https://doi.org/10.7554/eLife.83793
Further reading
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Niemann–Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.
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