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Author Notes:

Correspondence to Lih-Shen Chin: chinl@pharm.emory.edu; or Lian Li: lianli@ pharm.emory.edu

We thank Yifei Pu for assistance with yeast two-hybrid screens and James Olzmann for the SIMPLE–TSG101 colocalization analysis.

Subject:

Research Funding:

This work was supported by the National Institutes of Health (NIH; NS063501 to S.M. Lee, AG034126 to L.-S. Chin, ES015813 and GM082828 to L. Li) and the Emory University Research Committee (SK38167 to L.-S. Chin).

We thank Emory Neuroscience Imaging Core Facility (supported in part by NIH grant NS055077) for providing instrumentation and support.

Charcot-Marie-Tooth disease-linked protein SIMPLE functions with the ESCRT machinery in endosomal trafficking

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Journal Title:

Journal of Cell Biology

Volume:

Volume 199, Number 5

Publisher:

, Pages 799-816

Type of Work:

Article | Final Publisher PDF

Abstract:

Mutations in small integral membrane protein of lysosome/late endosome (SIMPLE) cause autosomal dominant, Charcot-Marie-Tooth disease (CMT) type 1C. The cellular function of SIMPLE is unknown and the pathogenic mechanism of SIMPLE mutations remains elusive. Here, we report that SIMPLE interacted and colocalized with endosomal sorting complex required for transport (ESCRT) components STAM1, Hrs, and TSG101 on early endosomes and functioned with the ESCRT machinery in the control of endosome-to-lysosome trafficking. Our analyses revealed that SIMPLE was required for efficient recruitment of ESCRT components to endosomal membranes and for regulating endosomal trafficking and signaling attenuation of ErbB receptors. We found that the ability of SIMPLE to regulate ErbB trafficking and signaling was impaired by CMT-linked SIMPLE mutations via a loss-of-function, dominant-negative mechanism, resulting in prolonged activation of ERK1/2 signaling. Our findings indicate a function of SIMPLE as a regulator of endosomal trafficking and provide evidence linking dysregulated endosomal trafficking to CMT pathogenesis.

Copyright information:

© 2012 Lee et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License (http://creativecommons.org/licenses/by-nc-sa/3.0/).

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