MTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide

Akinobu Matsumoto, Alessandra Pasut, Masaki Matsumoto, Riu Yamashita, Jacqueline Fung, Emanuele Monteleone, Alan Saghatelian, Keiichi Nakayama, John G. Clohessy, Pier Paolo Pandolfi

研究成果: ジャーナルへの寄稿記事

139 引用 (Scopus)

抄録

Although long non-coding RNAs (lncRNAs) are non-protein-coding transcripts by definition, recent studies have shown that a fraction of putative small open reading frames within lncRNAs are translated. However, the biological significance of these hidden polypeptides is still unclear. Here we identify and functionally characterize a novel polypeptide encoded by the lncRNA LINC00961. This polypeptide is conserved between human and mouse, is localized to the late endosome/lysosome and interacts with the lysosomal v-ATPase to negatively regulate mTORC1 activation. This regulation of mTORC1 is specific to activation of mTORC1 by amino acid stimulation, rather than by growth factors. Hence, we termed this polypeptide â small regulatory polypeptide of amino acid response' (SPAR). We show that the SPAR-encoding lncRNA is highly expressed in a subset of tissues and use CRISPR/Cas9 engineering to develop a SPAR-polypeptide-specific knockout mouse while maintaining expression of the host lncRNA. We find that the SPAR-encoding lncRNA is downregulated in skeletal muscle upon acute injury, and using this in vivo model we establish that SPAR downregulation enables efficient activation of mTORC1 and promotes muscle regeneration. Our data provide a mechanism by which mTORC1 activation may be finely regulated in a tissue-specific manner in response to injury, and a paradigm by which lncRNAs encoding small polypeptides can modulate general biological pathways and processes to facilitate tissue-specific requirements, consistent with their restricted and highly regulated expression profile.

元の言語英語
ページ(範囲)228-232
ページ数5
ジャーナルNature
541
発行部数7636
DOI
出版物ステータス出版済み - 1 12 2017

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Long Noncoding RNA
Regeneration
Amino Acids
Muscles
Peptides
Down-Regulation
Clustered Regularly Interspaced Short Palindromic Repeats
Aminoacylation
Biological Phenomena
Endosomes
Wounds and Injuries
Lysosomes
Knockout Mice
Open Reading Frames
Adenosine Triphosphatases
Intercellular Signaling Peptides and Proteins
Skeletal Muscle
mechanistic target of rapamycin complex 1

All Science Journal Classification (ASJC) codes

  • General

これを引用

Matsumoto, A., Pasut, A., Matsumoto, M., Yamashita, R., Fung, J., Monteleone, E., ... Pandolfi, P. P. (2017). MTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide. Nature, 541(7636), 228-232. https://doi.org/10.1038/nature21034

MTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide. / Matsumoto, Akinobu; Pasut, Alessandra; Matsumoto, Masaki; Yamashita, Riu; Fung, Jacqueline; Monteleone, Emanuele; Saghatelian, Alan; Nakayama, Keiichi; Clohessy, John G.; Pandolfi, Pier Paolo.

:: Nature, 巻 541, 番号 7636, 12.01.2017, p. 228-232.

研究成果: ジャーナルへの寄稿記事

Matsumoto, A, Pasut, A, Matsumoto, M, Yamashita, R, Fung, J, Monteleone, E, Saghatelian, A, Nakayama, K, Clohessy, JG & Pandolfi, PP 2017, 'MTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide', Nature, 巻. 541, 番号 7636, pp. 228-232. https://doi.org/10.1038/nature21034
Matsumoto, Akinobu ; Pasut, Alessandra ; Matsumoto, Masaki ; Yamashita, Riu ; Fung, Jacqueline ; Monteleone, Emanuele ; Saghatelian, Alan ; Nakayama, Keiichi ; Clohessy, John G. ; Pandolfi, Pier Paolo. / MTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide. :: Nature. 2017 ; 巻 541, 番号 7636. pp. 228-232.
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abstract = "Although long non-coding RNAs (lncRNAs) are non-protein-coding transcripts by definition, recent studies have shown that a fraction of putative small open reading frames within lncRNAs are translated. However, the biological significance of these hidden polypeptides is still unclear. Here we identify and functionally characterize a novel polypeptide encoded by the lncRNA LINC00961. This polypeptide is conserved between human and mouse, is localized to the late endosome/lysosome and interacts with the lysosomal v-ATPase to negatively regulate mTORC1 activation. This regulation of mTORC1 is specific to activation of mTORC1 by amino acid stimulation, rather than by growth factors. Hence, we termed this polypeptide {\^a} small regulatory polypeptide of amino acid response' (SPAR). We show that the SPAR-encoding lncRNA is highly expressed in a subset of tissues and use CRISPR/Cas9 engineering to develop a SPAR-polypeptide-specific knockout mouse while maintaining expression of the host lncRNA. We find that the SPAR-encoding lncRNA is downregulated in skeletal muscle upon acute injury, and using this in vivo model we establish that SPAR downregulation enables efficient activation of mTORC1 and promotes muscle regeneration. Our data provide a mechanism by which mTORC1 activation may be finely regulated in a tissue-specific manner in response to injury, and a paradigm by which lncRNAs encoding small polypeptides can modulate general biological pathways and processes to facilitate tissue-specific requirements, consistent with their restricted and highly regulated expression profile.",
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AU - Fung, Jacqueline

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