K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression

Zhenyue Hao; Yi Sheng; Gordon S. Duncan; Wanda Y. Li; Carmen Dominguez; Jennifer Sylvester; Yu Wen Su; Gloria H.Y. Lin; Bryan E. Snow; Dirk Brenner; Annick You-Ten; Jillian Haight; Satoshi Inoue; Andrew Wakeham; Alisha Elford; Sara Hamilton; Yi Liang; Juan C. Zúñiga-Pflücker; Housheng Hansen He; Pamela S. Ohashi; Tak W. Mak

doi:10.1038/ncomms14003

K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression

Zhenyue Hao, Yi Sheng, Gordon S. Duncan, Wanda Y. Li, Carmen Dominguez, Jennifer Sylvester, Yu Wen Su, Gloria H.Y. Lin, Bryan E. Snow, Dirk Brenner, Annick You-Ten, Jillian Haight, Satoshi Inoue, Andrew Wakeham, Alisha Elford, Sara Hamilton, Yi Liang, Juan C. Zúñiga-Pflücker, Housheng Hansen He, Pamela S. OhashiTak W. Mak

Research output: Contribution to journal › Article › peer-review

Abstract

T-cell proliferation is regulated by ubiquitination but the underlying molecular mechanism remains obscure. Here we report that Lys-48-linked ubiquitination of the transcription factor KLF4 mediated by the E3 ligase Mule promotes T-cell entry into S phase. Mule is elevated in T cells upon TCR engagement, and Mule deficiency in T cells blocks proliferation because KLF4 accumulates and drives upregulation of its transcriptional targets E2F2 and the cyclin-dependent kinase inhibitors p21 and p27. T-cell-specific Mule knockout (TMKO) mice develop exacerbated experimental autoimmune encephalomyelitis (EAE), show impaired generation of antigen-specific CD8 + T cells with reduced cytokine production, and fail to clear LCMV infections. Thus, Mule-mediated ubiquitination of the novel substrate KLF4 regulates T-cell proliferation, autoimmunity and antiviral immune responses in vivo.

Original language	English
Article number	14003
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14003
Publication status	Published - 2017 Jan 13
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/ncomms14003

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Hao, Z., Sheng, Y., Duncan, G. S., Li, W. Y., Dominguez, C., Sylvester, J., Su, Y. W., Lin, G. H. Y., Snow, B. E., Brenner, D., You-Ten, A., Haight, J., Inoue, S., Wakeham, A., Elford, A., Hamilton, S., Liang, Y., Zúñiga-Pflücker, J. C., He, H. H., ... Mak, T. W. (2017). K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression. Nature communications, 8, [14003]. https://doi.org/10.1038/ncomms14003

Hao, Z, Sheng, Y, Duncan, GS, Li, WY, Dominguez, C, Sylvester, J, Su, YW, Lin, GHY, Snow, BE, Brenner, D, You-Ten, A, Haight, J, Inoue, S, Wakeham, A, Elford, A, Hamilton, S, Liang, Y, Zúñiga-Pflücker, JC, He, HH, Ohashi, PS & Mak, TW 2017, 'K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression', Nature communications, vol. 8, 14003. https://doi.org/10.1038/ncomms14003

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title = "K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression",

abstract = "T-cell proliferation is regulated by ubiquitination but the underlying molecular mechanism remains obscure. Here we report that Lys-48-linked ubiquitination of the transcription factor KLF4 mediated by the E3 ligase Mule promotes T-cell entry into S phase. Mule is elevated in T cells upon TCR engagement, and Mule deficiency in T cells blocks proliferation because KLF4 accumulates and drives upregulation of its transcriptional targets E2F2 and the cyclin-dependent kinase inhibitors p21 and p27. T-cell-specific Mule knockout (TMKO) mice develop exacerbated experimental autoimmune encephalomyelitis (EAE), show impaired generation of antigen-specific CD8 + T cells with reduced cytokine production, and fail to clear LCMV infections. Thus, Mule-mediated ubiquitination of the novel substrate KLF4 regulates T-cell proliferation, autoimmunity and antiviral immune responses in vivo.",

author = "Zhenyue Hao and Yi Sheng and Duncan, {Gordon S.} and Li, {Wanda Y.} and Carmen Dominguez and Jennifer Sylvester and Su, {Yu Wen} and Lin, {Gloria H.Y.} and Snow, {Bryan E.} and Dirk Brenner and Annick You-Ten and Jillian Haight and Satoshi Inoue and Andrew Wakeham and Alisha Elford and Sara Hamilton and Yi Liang and Z{\'u}{\~n}iga-Pfl{\"u}cker, {Juan C.} and He, {Housheng Hansen} and Ohashi, {Pamela S.} and Mak, {Tak W.}",

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doi = "10.1038/ncomms14003",

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AU - Hao, Zhenyue

AU - Sheng, Yi

AU - Duncan, Gordon S.

AU - Li, Wanda Y.

AU - Dominguez, Carmen

AU - Sylvester, Jennifer

AU - Su, Yu Wen

AU - Lin, Gloria H.Y.

AU - Snow, Bryan E.

AU - Brenner, Dirk

AU - You-Ten, Annick

AU - Haight, Jillian

AU - Inoue, Satoshi

AU - Wakeham, Andrew

AU - Elford, Alisha

AU - Hamilton, Sara

AU - Liang, Yi

AU - Zúñiga-Pflücker, Juan C.

AU - He, Housheng Hansen

AU - Ohashi, Pamela S.

AU - Mak, Tak W.

PY - 2017/1/13

Y1 - 2017/1/13

N2 - T-cell proliferation is regulated by ubiquitination but the underlying molecular mechanism remains obscure. Here we report that Lys-48-linked ubiquitination of the transcription factor KLF4 mediated by the E3 ligase Mule promotes T-cell entry into S phase. Mule is elevated in T cells upon TCR engagement, and Mule deficiency in T cells blocks proliferation because KLF4 accumulates and drives upregulation of its transcriptional targets E2F2 and the cyclin-dependent kinase inhibitors p21 and p27. T-cell-specific Mule knockout (TMKO) mice develop exacerbated experimental autoimmune encephalomyelitis (EAE), show impaired generation of antigen-specific CD8 + T cells with reduced cytokine production, and fail to clear LCMV infections. Thus, Mule-mediated ubiquitination of the novel substrate KLF4 regulates T-cell proliferation, autoimmunity and antiviral immune responses in vivo.

AB - T-cell proliferation is regulated by ubiquitination but the underlying molecular mechanism remains obscure. Here we report that Lys-48-linked ubiquitination of the transcription factor KLF4 mediated by the E3 ligase Mule promotes T-cell entry into S phase. Mule is elevated in T cells upon TCR engagement, and Mule deficiency in T cells blocks proliferation because KLF4 accumulates and drives upregulation of its transcriptional targets E2F2 and the cyclin-dependent kinase inhibitors p21 and p27. T-cell-specific Mule knockout (TMKO) mice develop exacerbated experimental autoimmune encephalomyelitis (EAE), show impaired generation of antigen-specific CD8 + T cells with reduced cytokine production, and fail to clear LCMV infections. Thus, Mule-mediated ubiquitination of the novel substrate KLF4 regulates T-cell proliferation, autoimmunity and antiviral immune responses in vivo.

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K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression

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