TRPV4-dependent induction of a novel mammalian cold-inducible protein SRSF5 as well as CIRP and RBM3

Abstract

Cold-inducible RNA-binding protein (CIRP) and RNA-binding motif protein 3 (RBM3) are two evolutionarily conserved RNA-binding proteins that are structurally related to hnRNPs and upregulated in response to moderately low temperatures in mammalian cells. Although contributions of splicing efficiency, the gene promoters activated upon mild hypothermia and the transcription factor Sp1 to induction of CIRP have been reported, precise mechanisms by which hypothermia and other stresses induce the expression of mammalian cold-inducible proteins (CIPs) are poorly understood. By screening the serine/arginine-rich splicing factors (SRSFs), we report that the transcript and protein levels of SRSF5 were increased in mammalian cells cultured at 32 °C. Expression of SRSF5 as well as CIRP and RBM3 were also induced by DNA damage, hypoxia, cycloheximide and hypotonicity. Immunohistochemical studies demonstrated that SRSF5 was constitutively expressed in male germ cells and the level was decreased in human testicular germ cell tumors. SRSF5 facilitated production of p19 H-RAS, and increased sensitivity to doxorubicin in human U-2 OS cells. Induction of CIPs was dependent on transient receptor potential vanilloid 4 (TRPV4) channel protein, but seemed independent of its ion channel activity. These findings indicate a previously unappreciated role for the TRP protein in linking environmental stress to splicing.

Recent progress in the research of cold-inducible RNA-binding protein

“…Taken together, these results suggest that the regulation of CIRP expression in response to stress may be coordinated at multiple levels such as transcriptional activation, alternative splicing and splicing efficiency, either independently or collaboratively. More recently, a study using hypothermia-treated cells suggested a role of intracellular Ca 2+ levels in regulating CIRP expression in response to cold stress [ 24 ], suggesting that intracellular calcium signaling may be involved in CIRP regulation.…”

Extracellular CIRP (eCIRP) and inflammation

“…Recently, the overexpression of miRNA‐23a has also been shown to induce the expression of CIRP during prolonged hypoxia condition, possibly through its binding to CIRP's transcriptional enhancer . A recent study also revealed that hypothermia increases intracellular calcium levels via TRPV4, which regulates CIRP's expression in response to cold stress . CIRP has various transcripts, which possibly differ between species and may have responded differently to inducers, enhancers, and repressors .…”

The Expression of Cold-Inducible RNA-Binding Protein mRNA in Sow Genital Tract Is Modulated by Natural Mating, But Not by Seminal Plasma

“…Of the total number of DEGs encoding for RBP family included in the study (26 genes, Table 1 ), only two genes belong to the CIPs: CIRBP and SRSF5 [ 16 , 17 ]. The NM group up-regulated CIRBP mRNA expression in the cervix, utero-tubal junction, ampulla, and infundibulum ( p < 0.05), and up-regulated SRSF5 mRNA expression in the utero-tubal junction ( p < 0.05), whereas Semen-AI down-regulated SRSF5 mRNA expression in the cervix ( p < 0.05) and SP-AI up-regulated SRSF5 mRNA expression in the infundibulum ( p < 0.05).…”

“…The cold-inducible proteins (CIPs) are evolutionarily conserved RBPs that have been detected in multiple organisms from different taxa [ 15 ]. The cold-inducible RNA-binding protein (CIRBP, also known as CIRP, or heterogenous nuclear ribonucleoprotein A18, hnRNP A18), the RNA-binding motif protein 3 (RBM3), and the serine and arginine-rich splicing factor 5 (SRSF5, also known as SRp40) are CIPs transcriptionally up-regulated in response to moderately low temperatures and other cellular stressors, such as hypoxia, DNA damage, or osmotic stress [ 16 , 17 ].…”

“…The induction of CIPs is dependent on transient receptor potential (TRP) V4, V3, and M8 ion channel proteins [ 16 , 25 ]. The TRP mammalian proteins can be classified in four major families [ 26 ]: the ankyrin-related TRP channel family (TRPA), the TRPC family (classical or canonical), the melastatin-related TRP channel family (TRPM), and the channels homologous to vanilloid receptor (TRPV).…”