HuR counteracts miR-330 to promote STAT3 translation during inflammation-induced muscle wasting

Souad Mubaid, Jennifer F. Ma, Amr Omer, Kholoud Ashour, Xian J. Lian, Brenda J. Sanchez, Samantha Robinson, Anne Cammas, Virginie Dormoy-Raclet, Sergio Di Marco, Sridar V. Chittur, Scott A. Tenenbaum, Imed Gallouzi

Research output: Contribution to journalArticle

Abstract

Debilitating cancer-induced muscle wasting, a syndrome known as cachexia, is lethal. Here we report a posttranscriptional pathway involving the RNA-binding protein HuR as a key player in the onset of this syndrome. Under these conditions, HuR switches its function from a promoter of muscle fiber formation to become an inducer of muscle loss. HuR binds to the STAT3 (signal transducer and activator of transcription 3) mRNA, which encodes one of the main effectors of this condition, promoting its expression both in vitro and in vivo. While HuR does not affect the stability and the cellular movement of this transcript, HuR promotes the translation of the STAT3 mRNA by preventing miR-330 (microRNA 330)–mediated translation inhibition. To achieve this effect, HuR directly binds to a U-rich element in the STAT3 mRNA-3′untranslated region (UTR) located within the vicinity of the miR-330 seed element. Even though the binding sites of HuR and miR-330 do not overlap, the recruitment of either one of them to the STAT3-3′UTR negatively impacts the binding and the function of the other factor. Therefore, together, our data establish the competitive interplay between HuR and miR-330 as a mechanism via which muscle fibers modulate, in part, STAT3 expression to determine their fate in response to promoters of muscle wasting.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number35
DOIs
Publication statusPublished - 27 Aug 2019

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STAT3 Transcription Factor
MicroRNAs
Inflammation
Muscles
Messenger RNA
Muscle Neoplasms
Wasting Syndrome
Untranslated Regions
Cachexia
RNA-Binding Proteins
Seeds
Binding Sites

Keywords

  • HuR
  • MicroRNA
  • Muscle wasting
  • Posttranscriptional regulation
  • STAT3

ASJC Scopus subject areas

  • General

Cite this

HuR counteracts miR-330 to promote STAT3 translation during inflammation-induced muscle wasting. / Mubaid, Souad; Ma, Jennifer F.; Omer, Amr; Ashour, Kholoud; Lian, Xian J.; Sanchez, Brenda J.; Robinson, Samantha; Cammas, Anne; Dormoy-Raclet, Virginie; Marco, Sergio Di; Chittur, Sridar V.; Tenenbaum, Scott A.; Gallouzi, Imed.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 35, 27.08.2019.

Research output: Contribution to journalArticle

Mubaid, S, Ma, JF, Omer, A, Ashour, K, Lian, XJ, Sanchez, BJ, Robinson, S, Cammas, A, Dormoy-Raclet, V, Marco, SD, Chittur, SV, Tenenbaum, SA & Gallouzi, I 2019, 'HuR counteracts miR-330 to promote STAT3 translation during inflammation-induced muscle wasting', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 35. https://doi.org/10.1073/pnas.1905172116
Mubaid, Souad ; Ma, Jennifer F. ; Omer, Amr ; Ashour, Kholoud ; Lian, Xian J. ; Sanchez, Brenda J. ; Robinson, Samantha ; Cammas, Anne ; Dormoy-Raclet, Virginie ; Marco, Sergio Di ; Chittur, Sridar V. ; Tenenbaum, Scott A. ; Gallouzi, Imed. / HuR counteracts miR-330 to promote STAT3 translation during inflammation-induced muscle wasting. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 35.
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AB - Debilitating cancer-induced muscle wasting, a syndrome known as cachexia, is lethal. Here we report a posttranscriptional pathway involving the RNA-binding protein HuR as a key player in the onset of this syndrome. Under these conditions, HuR switches its function from a promoter of muscle fiber formation to become an inducer of muscle loss. HuR binds to the STAT3 (signal transducer and activator of transcription 3) mRNA, which encodes one of the main effectors of this condition, promoting its expression both in vitro and in vivo. While HuR does not affect the stability and the cellular movement of this transcript, HuR promotes the translation of the STAT3 mRNA by preventing miR-330 (microRNA 330)–mediated translation inhibition. To achieve this effect, HuR directly binds to a U-rich element in the STAT3 mRNA-3′untranslated region (UTR) located within the vicinity of the miR-330 seed element. Even though the binding sites of HuR and miR-330 do not overlap, the recruitment of either one of them to the STAT3-3′UTR negatively impacts the binding and the function of the other factor. Therefore, together, our data establish the competitive interplay between HuR and miR-330 as a mechanism via which muscle fibers modulate, in part, STAT3 expression to determine their fate in response to promoters of muscle wasting.

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