Department of Immunology and Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, Krakow, Poland.
Department of Inflammation and Immunity, Cleveland Clinic, Lerner Research Institute, Cleveland, Ohio, USA.
J Interferon Cytokine Res. 2022 Sep;42(9):482-492. doi: 10.1089/jir.2022.0095. Epub 2022 Jul 27.
Colorectal carcinoma is the leading cause of cancer-related death. Previously we have shown that tumor suppressor single immunoglobulin interleukin-1-related receptor (SIGIRR) is frequently inactivated in human colorectal cancer by the increased expression of a novel SIGIRR isoform (SIGIRR). SIGIRR showed increased retention in the cytoplasm and loss of complex glycan modification compared to the full-length SIGIRR. Now we found that the arginine residues located in the C-terminus of SIGIRR serve as an endoplasmic reticulum retention signal and are required for resident protein ribophorin 1 (RPN1) interaction. In addition, we found that SIGIRR exerts a direct impact on cell metabolism through interaction with the adenosine triphosphate synthase in the colorectal cancer cells. SIGIRR expression promoted the metabolic shift through upregulation of mammalian target of rapamycin signaling pathway and dysregulation of mitochondrial function to promote survival and proliferation of colon cancer cells in xenograft model.
结直肠癌是癌症相关死亡的主要原因。我们之前已经表明，肿瘤抑制因子单免疫球蛋白白细胞介素 1 相关受体（SIGIRR）在人类结直肠癌中经常通过新型 SIGIRR 同种型（SIGIRR）的表达增加而失活。与全长 SIGIRR 相比，SIGIRR 在细胞质中的保留增加，并且复杂糖基化修饰丢失。现在我们发现，SIGIRR 中位于 C 末端的精氨酸残基作为内质网保留信号，并且需要与驻留蛋白核糖体蛋白 1（RPN1）相互作用。此外，我们发现，SIGIRR 通过与结直肠癌细胞中的三磷酸腺苷合酶相互作用，对细胞代谢产生直接影响。SIGIRR 表达通过上调雷帕霉素靶蛋白信号通路和调节线粒体功能来促进代谢转变，从而促进异种移植模型中结肠癌细胞的存活和增殖。
