Argonaute Utilization for miRNA Silencing Is Determined by Phosphorylation-Dependent Recruitment of LIM-Domain-Containing Proteins

Katherine S. Bridge, Kunal M. Shah, Yigen Li, Daniel E. Foxler, Sybil C.K. Wong, Duncan C. Miller, Kathryn M. Davidson, John G. Foster, Ruth Rose, Michael R. Hodgkinson, Paulo S. Ribeiro, A. Aziz Aboobaker, Kenta Yashiro, Xiaozhong Wang, Paul R. Graves, Michael J. Plevin, Dimitris Lagos, Tyson V. Sharp*

*Corresponding author for this work

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

As core components of the microRNA-induced silencing complex (miRISC), Argonaute (AGO) proteins interact with TNRC6 proteins, recruiting other effectors of translational repression/mRNA destabilization. Here, we show that LIMD1 coordinates the assembly of an AGO-TNRC6 containing miRISC complex by binding both proteins simultaneously at distinct interfaces. Phosphorylation of AGO2 at Ser 387 by Akt3 induces LIMD1 binding, which in turn enables AGO2 to interact with TNRC6A and downstream effector DDX6. Conservation of this serine in AGO1 and 4 indicates this mechanism may be a fundamental requirement for AGO function and miRISC assembly. Upon CRISPR-Cas9-mediated knockout of LIMD1, AGO2 miRNA-silencing function is lost and miRNA silencing becomes dependent on a complex formed by AGO3 and the LIMD1 family member WTIP. The switch to AGO3 utilization occurs due to the presence of a glutamic acid residue (E390) on the interaction interface, which allows AGO3 to bind to LIMD1, AJUBA, and WTIP irrespective of Akt signaling.

Original languageEnglish (US)
Pages (from-to)173-187
Number of pages15
JournalCell reports
Volume20
Issue number1
DOIs
StatePublished - Jul 5 2017

Keywords

  • AGO2
  • AKT
  • Argonaute
  • DDX6
  • GW182
  • LIMD1
  • TNRC6A
  • WTIP
  • miRISC
  • microRNA

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Bridge, K. S., Shah, K. M., Li, Y., Foxler, D. E., Wong, S. C. K., Miller, D. C., Davidson, K. M., Foster, J. G., Rose, R., Hodgkinson, M. R., Ribeiro, P. S., Aboobaker, A. A., Yashiro, K., Wang, X., Graves, P. R., Plevin, M. J., Lagos, D., & Sharp, T. V. (2017). Argonaute Utilization for miRNA Silencing Is Determined by Phosphorylation-Dependent Recruitment of LIM-Domain-Containing Proteins. Cell reports, 20(1), 173-187. https://doi.org/10.1016/j.celrep.2017.06.027