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Roquin binds microRNA-146a and Argonaute2 to regulate microRNA homeostasis

Journal Article


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Abstract


  • Roquin is an RNA-binding protein that prevents autoimmunity and inflammation via repression of bound target mRNAs such as inducible costimulator (Icos). When Roquin is absent or mutated (Roquinsan), Icos is overexpressed in T cells. Here we show that Roquin enhances Dicer-mediated processing of pre-miR-146a. Roquin also directly binds Argonaute2, a central component of the RNA-induced silencing complex, and miR-146a, a microRNA that targets Icos mRNA. In the absence of functional Roquin, miR-146a accumulates in T cells. Its accumulation is not due to increased transcription or processing, rather due to enhanced stability of mature miR-146a. This is associated with decreased 3′ end uridylation of the miRNA. Crystallographic studies reveal that Roquin contains a unique HEPN domain and identify the structural basis of the ‘san’ mutation and Roquin’s ability to bind multiple RNAs. Roquin emerges as a protein that can bind Ago2, miRNAs and target mRNAs, to control homeostasis of both RNA species.

Authors


  •   Srivastava, Monika (external author)
  •   Duan, Guowen (external author)
  •   Kershaw, Nadia J. (external author)
  •   Athanasopoulos, Vicki (external author)
  •   Yeo, Janet H. (external author)
  •   Ose, Toyoyuki (external author)
  •   Hu, Desheng (external author)
  •   Brown, Simon H. J.
  •   Jergic, Slobodan
  •   Patel, Hardip R. (external author)
  •   Pratama, Alvin (external author)
  •   Richards, Sashika (external author)
  •   Verma, Anil (external author)
  •   Jones, E Yvonne. (external author)
  •   Heissmeyer, Vigo (external author)
  •   Preiss, Thomas (external author)
  •   Dixon, Nicholas E.
  •   Chong, Mark M. (external author)
  •   Babon, Jeffrey J. (external author)
  •   Vinuesa, Carola (external author)

Publication Date


  • 2015

Citation


  • Srivastava, M., Duan, G., Kershaw, N. J., Athanasopoulos, V., Yeo, J. H. C., Ose, T., Hu, D., Brown, S. H. J., Jergic, S., Patel, H. R., Pratama, A., Richards, S., Verma, A., Jones, E. Yvonne., Heissmeyer, V., Preiss, T., Dixon, N. E., Chong, M. M. W., Babon, J. J. & Vinuesa, C. G. (2015). Roquin binds microRNA-146a and Argonaute2 to regulate microRNA homeostasis. Nature Communications, 6 (February), 6253-1-6253-13.

Scopus Eid


  • 2-s2.0-84923345886

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1542&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/524

Has Global Citation Frequency


Start Page


  • 6253-1

End Page


  • 6253-13

Volume


  • 6

Issue


  • February

Place Of Publication


  • United Kingdom

Abstract


  • Roquin is an RNA-binding protein that prevents autoimmunity and inflammation via repression of bound target mRNAs such as inducible costimulator (Icos). When Roquin is absent or mutated (Roquinsan), Icos is overexpressed in T cells. Here we show that Roquin enhances Dicer-mediated processing of pre-miR-146a. Roquin also directly binds Argonaute2, a central component of the RNA-induced silencing complex, and miR-146a, a microRNA that targets Icos mRNA. In the absence of functional Roquin, miR-146a accumulates in T cells. Its accumulation is not due to increased transcription or processing, rather due to enhanced stability of mature miR-146a. This is associated with decreased 3′ end uridylation of the miRNA. Crystallographic studies reveal that Roquin contains a unique HEPN domain and identify the structural basis of the ‘san’ mutation and Roquin’s ability to bind multiple RNAs. Roquin emerges as a protein that can bind Ago2, miRNAs and target mRNAs, to control homeostasis of both RNA species.

Authors


  •   Srivastava, Monika (external author)
  •   Duan, Guowen (external author)
  •   Kershaw, Nadia J. (external author)
  •   Athanasopoulos, Vicki (external author)
  •   Yeo, Janet H. (external author)
  •   Ose, Toyoyuki (external author)
  •   Hu, Desheng (external author)
  •   Brown, Simon H. J.
  •   Jergic, Slobodan
  •   Patel, Hardip R. (external author)
  •   Pratama, Alvin (external author)
  •   Richards, Sashika (external author)
  •   Verma, Anil (external author)
  •   Jones, E Yvonne. (external author)
  •   Heissmeyer, Vigo (external author)
  •   Preiss, Thomas (external author)
  •   Dixon, Nicholas E.
  •   Chong, Mark M. (external author)
  •   Babon, Jeffrey J. (external author)
  •   Vinuesa, Carola (external author)

Publication Date


  • 2015

Citation


  • Srivastava, M., Duan, G., Kershaw, N. J., Athanasopoulos, V., Yeo, J. H. C., Ose, T., Hu, D., Brown, S. H. J., Jergic, S., Patel, H. R., Pratama, A., Richards, S., Verma, A., Jones, E. Yvonne., Heissmeyer, V., Preiss, T., Dixon, N. E., Chong, M. M. W., Babon, J. J. & Vinuesa, C. G. (2015). Roquin binds microRNA-146a and Argonaute2 to regulate microRNA homeostasis. Nature Communications, 6 (February), 6253-1-6253-13.

Scopus Eid


  • 2-s2.0-84923345886

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1542&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/524

Has Global Citation Frequency


Start Page


  • 6253-1

End Page


  • 6253-13

Volume


  • 6

Issue


  • February

Place Of Publication


  • United Kingdom