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

^*Corresponding author for this work

Experimental and Molecular Immunology

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

25 Citations (Scopus)

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 - 13 Jan 2017

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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

@article{cf754eab948c407e98aa58db8a66fb1d,

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.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2017.",

year = "2017",

month = jan,

day = "13",

doi = "10.1038/ncomms14003",

language = "English",

volume = "8",

journal = "Nature Communications",

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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

TY - JOUR

T1 - K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression

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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DO - 10.1038/ncomms14003

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AN - SCOPUS:85009436144

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 14003

ER -

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

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