Sec13 Regulates Expression of Specific Immune Factors Involved in Inflammation In Vivo

Thais G. Moreira; Liang Zhang; Lihi Shaulov; Amnon Harel; Sharon K. Kuss; Jessica Williams; John Shelton; Bandarigoda Somatilaka; Joachim Seemann; Jue Yang; Ramanavelan Sakthivel; Daniel R. Nussenzveig; Ana M.C. Faria; Beatriz M.A. Fontoura

doi:10.1038/srep17655

Sec13 Regulates Expression of Specific Immune Factors Involved in Inflammation In Vivo

Thais G. Moreira, Liang Zhang, Lihi Shaulov, Amnon Harel, Sharon K. Kuss, Jessica Williams, John Shelton, Bandarigoda Somatilaka, Joachim Seemann, Jue Yang, Ramanavelan Sakthivel, Daniel R. Nussenzveig, Ana M.C. Faria, Beatriz M.A. Fontoura

Bar-Ilan University - Azrieli Faculty of Medicine

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

21 Scopus citations

Abstract

The Sec13 protein functions in various intracellular compartments including the nuclear pore complex, COPII-coated vesicles, and inside the nucleus as a transcription regulator. Here we developed a mouse model that expresses low levels of Sec13 (Sec13^H/-) to assess its functions in vivo, as Sec13 knockout is lethal. These Sec13 mutant mice did not present gross defects in anatomy and physiology. However, the reduced levels of Sec13 in vivo yielded specific immunological defects. In particular, these Sec13 mutant mice showed low levels of MHC I and II expressed by macrophages, low levels of INF-γ and IL-6 expressed by stimulated T cells, and low frequencies of splenic IFN-γ+CD8+ T cells. In contrast, the levels of soluble and membrane-bound TGF-β as well as serum immunoglobulin production are high in these mice. Furthermore, frequencies of CD19+CD5-CD95+ and CD19+CD5-IL-4+B cells were diminished in Sec13^H/- mice. Upon stimulation or immunization, some of the defects observed in the naïve mutant mice were compensated. However, TGF-β expression remained high suggesting that Sec13 is a negative modulator of TGF-β expression and of its immunosuppressive functions on certain immune cells. In sum, Sec13 regulates specific expression of immune factors with key functions in inflammation.

Original language	English
Article number	17655
Journal	Scientific Reports
Volume	5
DOIs	https://doi.org/10.1038/srep17655
State	Published - 3 Dec 2015

Bibliographical note

Funding Information:
We thank the Electron Microscopy Facility and Metabolic Core Facility at UT Southwestern for TEM studies and biochemical measurements, respectively. Funding was provided by NIH R01 GM113874-01, R01 AI079110, R01 AI089539, CPRIT RP121003-RP120718-P2 to B.F; Israel Science Foundation (1072/10) to A.H.; NIH GM096070 to J.S.; Fellowship from CNPq Brasil to A.M.C.F. and Scholarship from FAPEMIG Brasil to T.G.M.

Funding

We thank the Electron Microscopy Facility and Metabolic Core Facility at UT Southwestern for TEM studies and biochemical measurements, respectively. Funding was provided by NIH R01 GM113874-01, R01 AI079110, R01 AI089539, CPRIT RP121003-RP120718-P2 to B.F; Israel Science Foundation (1072/10) to A.H.; NIH GM096070 to J.S.; Fellowship from CNPq Brasil to A.M.C.F. and Scholarship from FAPEMIG Brasil to T.G.M.

Funders	Funder number
National Institutes of Health	R01 AI079110, R01 GM113874-01
National Institute of Allergy and Infectious Diseases	R01AI089539
Cancer Prevention and Research Institute of Texas	RP121003-RP120718-P2
Conselho Nacional de Desenvolvimento Científico e Tecnológico
Israel Science Foundation	GM096070, 1072/10
Fundação de Amparo à Pesquisa do Estado de Minas Gerais

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Moreira, T. G., Zhang, L., Shaulov, L., Harel, A., Kuss, S. K., Williams, J., Shelton, J., Somatilaka, B., Seemann, J., Yang, J., Sakthivel, R., Nussenzveig, D. R., Faria, A. M. C., & Fontoura, B. M. A. (2015). Sec13 Regulates Expression of Specific Immune Factors Involved in Inflammation In Vivo. Scientific Reports, 5, Article 17655. https://doi.org/10.1038/srep17655

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title = "Sec13 Regulates Expression of Specific Immune Factors Involved in Inflammation In Vivo",

abstract = "The Sec13 protein functions in various intracellular compartments including the nuclear pore complex, COPII-coated vesicles, and inside the nucleus as a transcription regulator. Here we developed a mouse model that expresses low levels of Sec13 (Sec13H/-) to assess its functions in vivo, as Sec13 knockout is lethal. These Sec13 mutant mice did not present gross defects in anatomy and physiology. However, the reduced levels of Sec13 in vivo yielded specific immunological defects. In particular, these Sec13 mutant mice showed low levels of MHC I and II expressed by macrophages, low levels of INF-γ and IL-6 expressed by stimulated T cells, and low frequencies of splenic IFN-γ+CD8+ T cells. In contrast, the levels of soluble and membrane-bound TGF-β as well as serum immunoglobulin production are high in these mice. Furthermore, frequencies of CD19+CD5-CD95+ and CD19+CD5-IL-4+B cells were diminished in Sec13H/- mice. Upon stimulation or immunization, some of the defects observed in the na{\"i}ve mutant mice were compensated. However, TGF-β expression remained high suggesting that Sec13 is a negative modulator of TGF-β expression and of its immunosuppressive functions on certain immune cells. In sum, Sec13 regulates specific expression of immune factors with key functions in inflammation.",

author = "Moreira, {Thais G.} and Liang Zhang and Lihi Shaulov and Amnon Harel and Kuss, {Sharon K.} and Jessica Williams and John Shelton and Bandarigoda Somatilaka and Joachim Seemann and Jue Yang and Ramanavelan Sakthivel and Nussenzveig, {Daniel R.} and Faria, {Ana M.C.} and Fontoura, {Beatriz M.A.}",

note = "Funding Information: We thank the Electron Microscopy Facility and Metabolic Core Facility at UT Southwestern for TEM studies and biochemical measurements, respectively. Funding was provided by NIH R01 GM113874-01, R01 AI079110, R01 AI089539, CPRIT RP121003-RP120718-P2 to B.F; Israel Science Foundation (1072/10) to A.H.; NIH GM096070 to J.S.; Fellowship from CNPq Brasil to A.M.C.F. and Scholarship from FAPEMIG Brasil to T.G.M.",

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AU - Moreira, Thais G.

AU - Zhang, Liang

AU - Shaulov, Lihi

AU - Harel, Amnon

AU - Kuss, Sharon K.

AU - Williams, Jessica

AU - Shelton, John

AU - Somatilaka, Bandarigoda

AU - Seemann, Joachim

AU - Yang, Jue

AU - Sakthivel, Ramanavelan

AU - Nussenzveig, Daniel R.

AU - Faria, Ana M.C.

AU - Fontoura, Beatriz M.A.

N1 - Funding Information: We thank the Electron Microscopy Facility and Metabolic Core Facility at UT Southwestern for TEM studies and biochemical measurements, respectively. Funding was provided by NIH R01 GM113874-01, R01 AI079110, R01 AI089539, CPRIT RP121003-RP120718-P2 to B.F; Israel Science Foundation (1072/10) to A.H.; NIH GM096070 to J.S.; Fellowship from CNPq Brasil to A.M.C.F. and Scholarship from FAPEMIG Brasil to T.G.M.

PY - 2015/12/3

Y1 - 2015/12/3

N2 - The Sec13 protein functions in various intracellular compartments including the nuclear pore complex, COPII-coated vesicles, and inside the nucleus as a transcription regulator. Here we developed a mouse model that expresses low levels of Sec13 (Sec13H/-) to assess its functions in vivo, as Sec13 knockout is lethal. These Sec13 mutant mice did not present gross defects in anatomy and physiology. However, the reduced levels of Sec13 in vivo yielded specific immunological defects. In particular, these Sec13 mutant mice showed low levels of MHC I and II expressed by macrophages, low levels of INF-γ and IL-6 expressed by stimulated T cells, and low frequencies of splenic IFN-γ+CD8+ T cells. In contrast, the levels of soluble and membrane-bound TGF-β as well as serum immunoglobulin production are high in these mice. Furthermore, frequencies of CD19+CD5-CD95+ and CD19+CD5-IL-4+B cells were diminished in Sec13H/- mice. Upon stimulation or immunization, some of the defects observed in the naïve mutant mice were compensated. However, TGF-β expression remained high suggesting that Sec13 is a negative modulator of TGF-β expression and of its immunosuppressive functions on certain immune cells. In sum, Sec13 regulates specific expression of immune factors with key functions in inflammation.

AB - The Sec13 protein functions in various intracellular compartments including the nuclear pore complex, COPII-coated vesicles, and inside the nucleus as a transcription regulator. Here we developed a mouse model that expresses low levels of Sec13 (Sec13H/-) to assess its functions in vivo, as Sec13 knockout is lethal. These Sec13 mutant mice did not present gross defects in anatomy and physiology. However, the reduced levels of Sec13 in vivo yielded specific immunological defects. In particular, these Sec13 mutant mice showed low levels of MHC I and II expressed by macrophages, low levels of INF-γ and IL-6 expressed by stimulated T cells, and low frequencies of splenic IFN-γ+CD8+ T cells. In contrast, the levels of soluble and membrane-bound TGF-β as well as serum immunoglobulin production are high in these mice. Furthermore, frequencies of CD19+CD5-CD95+ and CD19+CD5-IL-4+B cells were diminished in Sec13H/- mice. Upon stimulation or immunization, some of the defects observed in the naïve mutant mice were compensated. However, TGF-β expression remained high suggesting that Sec13 is a negative modulator of TGF-β expression and of its immunosuppressive functions on certain immune cells. In sum, Sec13 regulates specific expression of immune factors with key functions in inflammation.

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Sec13 Regulates Expression of Specific Immune Factors Involved in Inflammation In Vivo

Abstract

Bibliographical note

Funding

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