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 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.

Role of Nucleoporins and Transport Receptors in Cell Differentiation

“…Mice with lower expression levels of Nup96 showed compromised T cell proliferation because of a decrease in the expression of interferon-regulated genes (Faria et al, 2006). Sec13 interacts with Nup96; therefore, the same trend was observed in a study conducted on mice with low levels of Sec13 (Moreira et al, 2015). Sec13 may have a role in the differentiation of retinal cells, according to a study conducted on Sec13 sq198 mutant zebrafish (Niu et al, 2014).…”

Nuclear pore complex-mediated modulation of TCR signaling is required for naïve CD4+ T cell homeostasis

“…Connections between NPCs and the immune system have recently emerged 42 , 43 , 44 , 45 . Mice heterozygous for the nucleoporins Nup96 and Sec13 show reduced levels of MHC class I and class II in APCs 43 , 44 . Decreased MHC expression in Nup96 +/− mice indirectly affects T cell expansion and the response to vesicular stomatitis virus infections 43 .…”

Integrity of the short arm of nuclear pore Y-complex is required for mouse embryonic stem cell growth and differentiation

“…(https://www.mousephenotype.org/data/genes/MGI:1919964) all Y-Nups genes inactivated so far in mice (namely Elys,Nup96,Nup133,Nup85,Sec13 and Seh1) lead to embryonic lethality (Faria et al, 2006;Liu et al, 2019;Lupu et al, 2008;Moreira et al, 2015;Okita et al, 2004;Terashima et al, 2020). In particular, Nup133 was found to be essential for mouse development beyond gastrulation (Lupu et al, 2008).…”