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 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.
Highlights
Nuclear import and export of molecules are vital cellular processes that occur through nuclear pore complexes (NPC)
We showed that Sec13H/− mice displayed a few similarities with Nup96+/− mice[7]
Both Sec13H/− and Nup96+/− mice presented selective defects in the expression of key IFNγ -regulated genes such as MHC expression. Both MHC class I and class II are regulated by cytokines including IFN-γ 26,27
Summary
Nuclear import and export of molecules are vital cellular processes that occur through nuclear pore complexes (NPC). Nup[160] mutant cells selectively reduced EDS1 levels, which is an important regulator of basal and TNL-triggered resistance These results imply that Nup[160] regulates proper expression of EDS1 and its functions in conditioned resistance pathways in plants, and that Nup[160] may be required for EDS1 activities in autoimmunity[10,11]. Sec13H/− mice showed elevated frequencies of LAP+ regulatory T (Treg) cells as well as decreased expression of IFNγ and of the pro-inflammatory cytokine IL-6 These results were accompanied by low protein levels of interferon-regulated genes such as MHC class I and MHC class II. These studies reveal specific immunosuppressive alterations in Sec13H/− mice that are known to impact inflammation
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