Unphosphorylated STAT1 represses apoptosis in macrophages during Mycobacterium tuberculosis infection

Abstract

In murine macrophages infected with Mycobacterium tuberculosis (Mtb), the level of phosphorylated STAT1 (PSTAT1) driving the expression of many pro-apoptosis genes, increases quickly but then declines over a period of hours. On the contrary, there is a continued increase of unphosphorylated STAT1 (USTAT1) that persists for several days. Similar trend is discovered between USTAT1 level and the intracellular bacterial burden during late infection. To investigate the significance of high level of USTAT1, we increased its concentration exogenously, and the apoptosis rate induced by Mtb is sufficiently decreased. Further experiment confirms USTAT1 affects the expression of several immune-associated gene, and lessens sensitivity of macrophages to CD95-mediated apoptosis during Mtb infection. Furthermore, we characterized 149 USTAT1-interacting proteins and the interactome network. The cooperation between USTAT1 and STAT3 results in downregulation of CD95 expression. Additionally, a competitive binding reactions between USTAT1 and IFIT1 to eEF1A was verified. Together, our data firstly show the USTAT1 differs from the PSTAT1, and represses apoptosis in macrophages to promote immune evasion during Mtb infection.