Regulation of cold-inducible RNA-binding protein (CIRBP) in response to cellular stresses

Cold-inducible RNA-Binding Protein (CIRBP) is a general stress-response factor in vertebrates harboring two domains: an RNA-recognition motif and a regulatory domain rich in RG/RGG motifs. CIRBP has been described to bind mRNAs upon various stress conditions (cold, infections, UV, hypoxia …) and regulate their stability and translation. The proteins encoded by its targets are involved in key stress-responsive cellular pathways including apoptosis, inflammation, cell proliferation or translation, thus allowing their coordination. Due to its role in regulating central cellular functions, the expression of CIRBP is tightly controlled. We review here current understanding of the multiple mechanistic layers affecting CIRBP expression and function. Beyond transcriptional regulation by cold-responsive elements and the use of alternative promoters and transcription start sites, CIRBP undergoes various alternative splicing (AS) events which, depending on conditions, modulate the stability of CIRBP transcripts and/or impact the sequence of the encoded polypeptide. Typically, whilst CIRBP expression is induced in the context of hypothermia or viral infection, AS events preferentially address alternative isoforms towards mRNA degradation pathways in response to heat stress or to bacterial-secreted pore forming toxins. Post-translational modifications of CIRBP, mostly in its RGG domain, also condition CIRBP subcellular localization and access to its targets, thereby promoting or inhibiting their expression. For instance, phosphorylation and methylation events gate CIRBP nuclear to cytoplasmic translocation and control its recruitment to stress granules. Considering the therapeutic potential of modulating the expression and function of this central player in stress responses, a fine understanding of CIRBP regulation mechanisms deserves further attention.