Loss of Perp in T Cells Promotes Resistance to Apoptosis of T Helper 17 Cells and Exacerbates the Development of Experimental Autoimmune Encephalomyelitis in Mice

Abstract

T helper 17 (Th17) cells are crucial for the pathogenesis of multiple sclerosis (MS) in humans and experimental autoimmune encephalomyelitis (EAE) in animals. High frequency of Th17 cells and low sensitivity to activation-induced cell death (AICD) are detected in MS patients. However, the mechanisms underlying apoptosis resistance of T cells remain unclear. Perp is an apoptosis-associated target of p53 and implicated in the development of cancers. Here, we show that loss of Perp in T cells does not affect Th1, Th17, or Treg cell differentiation, but does significantly increase the resistance of Perp−/− Th17 cells to AICD and anti-Fas in Lck-Cre × Perpfl/fl mice by inhibiting the caspase-dependent apoptotic pathway. Moreover, Lck-Cre × Perpfl/fl mice exhibited earlier onset of EAE and severe spinal cord inflammation and demyelination, accompanied by increased levels of pro-inflammatory cytokines and enlarged population of Th17 cells. Therefore, Perp deletion promoted Th17 responses and exacerbated the development and severity of EAE.

Insulin receptor substrate 1 gene expression is strongly up-regulated by HSPB8 silencing in U87 glioma cells

“…It is possible that these differences in functional significance of changes in HOMER3 expression level are due to the features of different tumors. At the same time, upregulation of PERP in cells treated by HSPB8 silencing does not agree with functional significance of this protein, because PERP has anti-proliferative properties, it induces apoptosis (Beaudry et al 2010;Awais et al 2016;Zhou et al 2018). Furthermore, our results showed that silencing of HSPB8 leads to a down-regulation of MYL9, PER2, and GADD45A gene expressions in glioma cells and these data agree with anti-tumor properties of proteins encoding by these genes (Cui et al 2017;Hacker et al 2018;Xiang et al 2018).…”

“…Among them: hexokinase 2 (HK2), glyoxalase 1 (GLO1), period circadian regulator 2 (PER2), growth arrest and DNA-damage-inducible, alpha (GADD45A), homer scaffolding protein 3 (HOMER3), nicotinamide phosphoribosyltransferase (NAMPT), myosin regulatory light chain 9 subunit (MYL9), TP53 apoptosis effector (PERP) and DEK proto-oncogene (DEK). These polyfunctional proteins play an important role in the regulation of cell proliferation and surviving (Shen et al 2016;Chiavarina et al 2017;Hacker et al 2018;Qu et al 2018;Xiong et al 2018;Zhou et al 2018;Chen et al 2014Chen et al , 2019Xie et al 2019). Thus, protein IRS1, which can interact with insulin receptor and IGF receptors, is stress responsible phosphorylated by insulin receptor tyrosine kinase.…”

“…The proteins encoding by PER2, HOMER3, GADD45A, and DEK genes, also involved in cancer cell proliferation and tumor growth, are dysregulated in cancer cells (Li et al 2013;Shen et al 2016;Hacker et al 2018;Xiang et al 2018;Xiong et al 2018;Rahman et al 2019). Protein PERP controls apoptosis, the marked increase in PERP expression induces apoptosis but loss of PERP protein promotes resistance to apoptosis as well as tumorigenesis (Beaudry et al 2010;Awais et al 2016;Zhou et al 2018). Myosin regulatory subunit plays an important role in the regulation of various processes and high level of MYL9 expression associates with poor prognosis in patients with glioblastoma and esophageal squamous cell carcinoma (Wang et al 2017;Kruthika et al 2019).…”

CPT-11 mitigates autoimmune diseases by suppressing effector T cells without affecting long-term anti-tumor immunity

“…Expression of Cdkn1a, Perp, Phlda1, and Tnf was upregulated in CPT-11-treated T cells (Fig. 4a, b ), and the proteins encoded by these genes have been shown to induce T cell apoptosis [ 18 – 21 ]. Moreover, expression of Gpr55, Tigit, and Zbtb32 was upregulated in CPT-11-treated T cells (Fig.…”