|Year : 2019 | Volume
| Issue : 3 | Page : 73-77
Multiple functions of cold-inducible RNA-binding protein in biological systems
Gang Li, Peixian Gao, Kun Luo, Hua Zhou, Yuxiang He, Hai Yuan, Xuejun Wu
Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
|Date of Submission||16-Feb-2019|
|Date of Acceptance||11-Apr-2019|
|Date of Web Publication||28-Nov-2019|
Prof. Xuejun Wu
Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, No. 324 of Jing Wu Wei Qi Road, Jinan, 250021
Source of Support: None, Conflict of Interest: None
Cold-inducible RNA-binding protein (CIRP) is an 18-kDa nuclear protein belonging to the family of cold-shock proteins. It is widely expressed in various tissues and upregulated in response to various cellular stresses. Originally, CIRP was found to stabilize specific mRNAs to facilitate their translation, which results in a survival advantage for cells under stress. Hypothermia-induced CIRP has been shown to protect the neuronal system. Recently, CIRP was found to be a multifunctional protein. In addition to acting as a damage-associated molecular pattern molecule to promote inflammation, it was also found to affect tumorigenesis. CIRP was also found to regulate telomerase activity and cardiac repolarization. Therefore, biological activities of CIRP in novel systems should receive more attention. This review will provide a brief introduction to the recent studies of CIRP with the aim of inspiring future research of novel CIRP functions.
Keywords: Cold-inducible RNA-binding protein, inflammation, stress, tumorigenesis
|How to cite this article:|
Li G, Gao P, Luo K, Zhou H, He Y, Yuan H, Wu X. Multiple functions of cold-inducible RNA-binding protein in biological systems. Vasc Invest Ther 2019;2:73-7
|How to cite this URL:|
Li G, Gao P, Luo K, Zhou H, He Y, Yuan H, Wu X. Multiple functions of cold-inducible RNA-binding protein in biological systems. Vasc Invest Ther [serial online] 2019 [cited 2019 Dec 14];2:73-7. Available from: http://www.vitonline.org/text.asp?2019/2/3/73/271903
| Introduction|| |
Cold-inducible RNA-binding protein (CIRP), also known as CIRBP and heterogeneous ribonucleoprotein (RNP) A18, is an 18-KDa nuclear protein. CIRP belongs to the family of cold-shock proteins. Both murine and human CIRPs have 172 residues with 95% similarity and contain two clearly defined domains: the N-terminal consensus sequence contains an RNA-binding domain (RBD) and the C-terminal consensus sequence contains a glycine-rich domain.,, The RBD is well conserved across many different species and binds to RNA. However, the function of the glycine-rich domain remains unknown.
CIRP was originally discovered in transcripts from mammalian cells after sustaining DNA damage (by ultraviolet [UV] irradiation or UV mimetic agents)., Subsequently, CIRP was found to be upregulated by a wide variety of cellular stressors, such as hypothermia and hypoxia.,, CIRP was also found to be widely expressed in various tissues that were not exposed to stressors, such as heart, liver, testes, and brain.,,,,,,,, CIRP is initially located in the nucleus, which migrates from the nucleus to the cytoplasm during the response to stress.,, Originally, CIRP was identified to stabilize specific mRNA to facilitate their translation, which results in a survival advantage for cell under stress.,, Xia et al. found that CIRP stabilized specific mRNAs to exhibit a protective effect against damage caused by testicular torsion/detorsion in experimental mice. Kaneko and Kibayashi  found that CIRP inhibited neurocyte apoptosis to protect stressed cells. Recently, many studies have indicated that CIRP is secreted to the extracellular environment where it acts as a damage-associated molecular pattern (DAMP) molecule that promotes inflammatory responses.,,, Moreover, anti-CIRP treatment has a protective effect in hemorrhagic shock, sepsis, liver ischemia/reperfusion injury, alcohol-induced brain injury, and cerebral ischemia. CIRP also displays an important role in tumorigenesis, such as colitis-associated cancer  and liver cancer.
Based on these studies, we think CIRP is a multifunctional protein that should receive more attention. The following section will briefly review the structure, subcellular localization, and recent studies of CIRP in different diseases, followed by the promising future gain from the intense CIRP research.
| The Structure and Subcellular Localization of Cold-Inducible RNA-Binding Protein|| |
There are two significant domains of CIRP: its N-terminal consensus sequence contains an RBD and its C-terminal consensus sequence contains a glycine-rich domain. RBD is one of the major RNA-binding motifs, also known as RNA recognition motif, RNP motif, or RNP consensus sequence.,, It includes two RNA-binding sites, an octamer designated RNP1 and a hexamer designated RNP2, which are well conserved across different species. Based on the presence of the RBD motif, CIRP also mediates RNA binding. Yang et al. found that CIRP could specifically bind to the 3'-untranslated region (UTR) of thioredoxin mRNA. CIRP also specifically binds the 3'-UTR of replication protein A and Ataxia telangiectasia-mutated and Rad3-related mRNA.,
The RNA-binding proteins play a very important role in regulating gene expression. In this process, the RNA-binding proteins are involved in various posttranscriptional aspects, such as nuclear/cytoplasmic transport, RNA localization, RNA stability, and translation. The mRNA translation is the key control point for cells under stress. Translation initiation can be regulated at both the 5' and the 3' end of an mRNA transcript. The RNA-binding proteins can also affect the stability of a transcript when binding to the 3'-UTR. Regulation of protein translation is recognized as the key point of the cellular response following stress. Moreover, modification of the protein synthesis patterns was recognized as an early change following stress. Downregulation of protein synthesis is an adaptive cellular response to stress, which conserves necessary resources for survival. CIRP binds the 5'-UTR or 3'-UTR of specific mRNAs and alters initiation of translation and/or the stability of the transcripts to facilitate their translation, which results in a survival advantage for cells under stress.,,,
The subcellular localization of CIRP is dependent on stress conditions., CIRP is primarily found in the nucleus of unstressed cells., Originally, CIRP was thought to remain in the nucleus of mammalian cells exposed to hypothermic shock. In contrast, De Leeuw et al. found that CIRP migrates from the nucleus to the cytoplasm under oxidative stress by a methylation-dependent mechanism. Yang and Carrier  also found that UV radiation triggered CIRP migration from the nucleus to the cytoplasm. Recently, Qiang et al. found that CIRP was secreted to extracellular in the hemorrhagic and septic shock. Now, increasing studies have found that CIRP is secreted to extracellular in response to different stresses.,
| The Multifunction of Cold-Inducible RNA-Binding Protein|| |
Originally, CIRP was found to be upregulated in response to UV irradiation or UV mimetic agents. Subsequently, Nishiyama et al. found that hypothermia could also facilitate the expression of CIRP in mammalian cells., Wellmann et al. found that CIRP was upregulated in response to the hypoxia by an hypoxia-inducible factor-1-independent mechanism. The increasing number of studies indicate that CIRP is upregulating in response to various cellular stressors and CIRP is a general stress-responsive protein.,,,
However, CIRP acts differently in various biological systems. Originally, CIRP was proposed to inhibit mammalian cell proliferation. Nishiyama et al. found that downregulation of CIRP using antisense oligodeoxynucleotides restored growth that was reduced by hypothermia, while overexpression of CIRP decreased the growth rate of mouse fibroblasts at 37°C through prolonging the G1 phase of the cell cycle. This research indicated that CIRP suppressed the growth of mouse fibroblasts. In contrast, Hong et al. found that downregulation of CIRP did not improve hypothermic growth of Chinese hamster ovary cells. Subsequently, Artero-Castro et al. found that CIRP stimulated proliferation of primary cells by upregulating extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation. Accordingly, downregulation of CIRP impaired cell proliferation and decreased ERK1/2 phosphorylation. Masuda et al. reported that CIRP promoted proliferation of immature male germ cells in mice. They also found that CIRP promoted cell cycle progression from G0–G1 to G–S phase in mouse embryonic fibroblasts. From these studies, CIRP seems to promote cell proliferation and might be involved with the cell cycle.
Recently, some studies indicated that CIRP played an important role in protecting cells against apoptosis.,, Sakurai et al. found that CIRP protected against tumor necrosis factor (TNF)-α-induced apoptosis of mouse fibroblasts both at 37°C and 32°C through activation of the ERK pathway. Li et al. also found that hypothermia-induced CIRP inhibited H2O2-induced apoptosis of rat cortical neurons and thereby exerted a neuroprotective effect. Their study examined one of the cerebral protective pathways under hypothermia. Other researchers also found that hypothermia-induced CIRP has a neuroprotective effect by suppressing the mitochondrial apoptosis pathway., This may be the molecular mechanism of hypothermia-induced neuroprotection. Recently, Liu et al. found that recombinant CIRP (rCIRP) significantly improved viability of nero2a cells following H2O2 stimulation. Hence, CIRP was identified as a neuroprotective cytokine. In addition to being a novel neuroprotective agent, CIRP also exhibited a testicular cell protective effect in testicular torsion/detorsion injury  and cryptorchidism-induced testicular damage. CIRP protects testes by regulating the stabilization of specific mRNAs in the testes of the experimental mice.
In contrast, recent studies have found that CIRP acts as a DAMP molecule with pro-inflammatory cytokine-like properties. Brochu et al. found that CIRP upregulated interleukin-1β expression in a variety of cell types under stress. Subsequently, Qiang et al. found that CIRP was secreted to the extracellular space and bound to the cell surface receptor TLR4 to trigger inflammatory responses in hemorrhagic shock and sepsis. They also found that the rCIRP stimulated TNF-α production in RAW 264.7 cells. Rajayer et al. demonstrated that alcohol could stimulate BV2 cells (mouse microglia) to secrete CIRP into the medium, and CIRP -/- mice had an attenuated inflammatory response following alcohol exposure. Zhou et al. showed that rCIRP directly stimulated TNF-α production in BV2 cells. In their study, the CIRP -/- mice showed attenuated inflammation and neuron injury in cerebral ischemia. Then, CIRP was also found to mediate inflammation in liver ischemia/reperfusion injury, colitis, and wound healing progression. Moreover, clinical studies have found that increased CIRP levels in peripheral blood is a potential predictor of poor prognosis during sepsis. Based on all these studies, CIRP was identified as a new pro-inflammatory cytokine.
| The Role of Cold-Inducible RNA-Binding Protein in Tumorigenesis|| |
Apoptosis is a crucial form of programmed cell death during development and homeostasis in both vertebrates and invertebrates. Apoptosis is also considered the major method of eradicating tumors. CIRP inhibits apoptosis by regulating p53 or suppressing mitochondrial apoptosis., In light of these observations, CIRP may be involved in tumorigenesis.
In a previous study, Artero-Castro et al. found that CIRP was upregulated in many tumors, such as liver-pancreas, gastric, nervous system, lung, kidney, ovarian, breast, colon, and prostate tumors. In their study, they also showed that central nervous system-related tumors have a significant correlation between P-ERK1/2 and CIRP (P = 0.05), and the association with liver-pancreas carcinomas approached significant levels (P = 0.08). Lleonart has recognized CIRP as a new proto-oncogene. Recently, Sakurai et al. found that CIRP mediated the tumorigenesis of colitis-associated cancer. In their research, CIRP -/- mice showed a significant decrease in the number and maximum size of tumors compared with wild-type (WT) mice in a colitis-associated cancer model. They also found that transplantation of CIRP -/- bone marrow into WT mice reduced tumorigenesis, indicating that CIRP promoted tumorigenesis through hematopoietic cells. Sakurai et al. also found that CIRP -/- mice had fewer and smaller tumors compared with WT mice in diethylnitrosamine-induced hepatocarcinogenesis. Their clinical study found that the risk of human hepatocellular carcinoma recurrence was positively correlated with CIRP expression in the liver. Wang et al. also found that the proliferation, invasion, and recurrence of pituitary adenomas were closely related to the high expression of CIRP. Subsequently, high expression of CIRP was found in oral squamous cell carcinoma and pituitary corticotroph adenoma and also closely correlates with the recurrence of these diseases., Without a doubt, CIRP affects tumorigenesis and should be further investigated in other tumors.
| Conclusion and Future Directions|| |
Here, we reviewed recent studies of CIRP. It is now widely accepted that CIRP is a multifunctional protein with many biological activities. However, the various biological activities of CIRP are not consistent. In most neuronal studies, hypothermia-induced CIRP showed a protective effect on the neuronal system. In contrast, Zhou et al. found that CIRP displayed pro-inflammatory cytokine-like properties in the cerebral ischemia. The role of CIRP in neuronal systems needs further research. Other studies highlight that CIRP acts as a pro-inflammatory cytokine and induces organ injury in many inflammation-associated diseases. In addition, CIRP partially affects tumorigenesis and was identified as a new oncogene. CIRP was found to regulate telomerase activity in a temperature-dependent manner  as well as regulating cardiac repolarization by targeting transient outward potassium channels. By now, it is evident that the role of CIRP in other biological activities should receive more attention.
Recently, Ren et al. found that TLR4 was coexpressed with CIRP in the oral squamous cell carcinoma. TLR4 is a cellular surface pattern-recognition receptor that mediates the innate immune response. It can recognize several endogenous molecules, such as HMGB1 and heat shock protein 70.,, Qiang et al. also found that CIRP interacts with TLR4 to induce inflammation in hemorrhagic shock and sepsis. In their study, TLR4-/- mice showed a significant attenuated organ injury following rCIRP infusion compared with the WT mice. These results suggest that TLR4 is the major receptor of CIRP. When TLR4 is activated, it activates intracellular signaling molecules through the MyD88-dependent or TRIF-dependent pathways that ultimately activate nuclear factor (NF)-κB to induce downstream cytokine expression. Zhou et al. found that rCIRP activates NF-κB and induces expression of its downstream cytokine (TNF-α). Brochu et al. found that CIRP upregulated interleukin-1β expression in an NF-κB-dependent manner. Furthermore, the TLR4/NF-κB-signaling pathway may mediate CIRP-associated biological activities and needs more attention in future studies.
This work was supported by grant from the National Natural Science Foundation of China (No. 8157020626; No. 81670435; No. 81800409), the Medicine and Health Science Technology Development Plan of Shandong (No. 2016WS0429), and the Major Research and Development Program of Shandong (No. 2017GSF218074).
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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