Regulation of WASH-dependent actin polymerization and protein trafficking by ubiquitination

Yi Heng Hao, Jennifer M. Doyle, Saumya Ramanathan, Timothy S. Gomez, Da Jia, Ming Xu, Zhijian J. Chen, Daniel D. Billadeau, Michael K. Rosen, Patrick Ryan Potts

Research output: Contribution to journalArticle

114 Scopus citations

Abstract

Endosomal protein trafficking is an essential cellular process that is deregulated in several diseases and targeted by pathogens. Here, we describe a role for ubiquitination in this process. We find that the E3 RING ubiquitin ligase, MAGE-L2-TRIM27, localizes to endosomes through interactions with the retromer complex. Knockdown of MAGE-L2-TRIM27 or the Ube2O E2 ubiquitin-conjugating enzyme significantly impaired retromer-mediated transport. We further demonstrate that MAGE-L2-TRIM27 ubiquitin ligase activity is required for nucleation of endosomal F-actin by the WASH regulatory complex, a known regulator of retromer-mediated transport. Mechanistic studies showed that MAGE-L2-TRIM27 facilitates K63-linked ubiquitination of WASH K220. Significantly, disruption of WASH ubiquitination impaired endosomal F-actin nucleation and retromer-dependent transport. These findings provide a cellular and molecular function for MAGE-L2-TRIM27 in retrograde transport, including an unappreciated role of K63-linked ubiquitination and identification of an activating signal of the WASH regulatory complex.

Original languageEnglish (US)
Pages (from-to)1051-1064
Number of pages14
JournalCell
Volume152
Issue number5
DOIs
StatePublished - Feb 28 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Hao, Y. H., Doyle, J. M., Ramanathan, S., Gomez, T. S., Jia, D., Xu, M., Chen, Z. J., Billadeau, D. D., Rosen, M. K., & Potts, P. R. (2013). Regulation of WASH-dependent actin polymerization and protein trafficking by ubiquitination. Cell, 152(5), 1051-1064. https://doi.org/10.1016/j.cell.2013.01.051