Work

The alternative polyadenylation factor CFIm25 orchestrates macrophage antibacterial activity against Salmonella through the TAB2 and TBL1XR1 regulators of MAPK and NF-κB signaling

Year: 2026

Type: article

Abstract: ABSTRACT Macrophage antimicrobial programs are regulated not only by transcriptional networks but also by RNA processing mechanisms affecting signal transduction and effector responses. One such mechanism, alternative polyadenylation (APA), determines mRNA fate by changing the length of the 3′ untranslated region (3′ UTR). However, our understanding of the impact of APA on antibacterial functions and how we can manipulate it to influence infection outcomes remains limited. In this study, we identify the APA regulator CFIm25 (NUDT21) as a promoter of macrophage defense against Salmonella enterica serovar Typhimurium (STM). STM infection drives macrophages toward an M2-like immunosuppressive state conducive to bacterial survival, and we show that CFIm25 levels are concurrently reduced during this transition. Overexpression of CFIm25 in infected macrophages blocks STM-induced 3′ UTR lengthening of the key immune regulators TAB2 and TBL1XR1, restoring their mRNA and protein expression. Sustained CFIm25 activity reduces intracellular bacterial burden, enhances macrophage survival, increases reactive oxygen species and nitric oxide production, suppresses arginase activity, and preserves M1-associated surface marker expression and pro-inflammatory cytokine secretion. Mechanistically, TAB2 and TBL1XR1 knockdown studies demonstrate that the antibacterial effects of CFIm25 depend on these CFIm25 targets, which are important for activating MAPK and NF-κB signaling pathways. Furthermore, CFIm25 depletion increased the recovery of intracellular STM from the infected cells. Together, these findings identify APA regulation as a potential target for boosting innate immune defenses against chronic bacterial infections.

Source: Infection and Immunity

DOI: 10.1128/iai.00361-26

Authors: Atish Barua, Srimoyee Mukherjee, Jeff Bourgeois, Claire L. Moore

Institutions: Tufts University, Worcester Polytechnic Institute

Language: English

Topic: RNA Research and Splicing

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: diamond

Funder: National Institutes of Health