The RNA-Binding Protein KSRP Is a Negative Regulator of Innate Immunity

KSRP (KH-type splicing regulatory protein) has emerged as a pivotal regulator of gene expression at multiple levels, acting as a transcription and splicing factor in the nucleus, and mediating AU-rich element (ARE)-dependent mRNA decay, translational silencing, and microRNA (miRNA) maturation in the cytoplasm. We and others have shown that KSRP acts as a regulator of immune responses, e.g., by dampening the expression of proinflammatory cytokines such as TNF-α, IL-6, IL-8, but also of NOS2, and facilitating the maturation of regulatory miRNAs, including let-7a, miR-129, and miR-155. This review aims to present current knowledge on the regulation of KSRP activity as conferred by miRNAs, phosphorylation, ubiquitination, SUMOylation, and interactions with long non-coding RNAs to enable dynamic responses towards inflammatory stimuli, and the effects of KSRP on innate immune reactions. Here, KSRP acts as an inhibitor by attenuating RIG-I-mediated antiviral signaling, cytokine production, and phagocytosis. In vivo, KSRP deficiency reduced arthritis severity but heightened inflammatory responses in sepsis and enhanced pathogen clearance in invasive pulmonary aspergillosis. These findings position KSRP as a dual regulator that limits tissue damage while constraining antimicrobial immunity. As a perspective, modulation of KSRP activity by applying pharmacological inhibitors may provide strategies to either suppress hyperinflammation in autoimmunity and sepsis or enhance host defense in immunocompromised states.