Cold-inducible RNA binding protein in cancer and inflammation

Abstract

RNA binding proteins (RBPs) play key roles in RNA dynamics, including subcellular localization, translational efficiency and metabolism. Cold-inducible RNA binding protein (CIRP) is a stress-induced protein that was initially described as a DNA damage-induced transcript (A18 hnRNP), as well as a cold-shock domain containing cold-stress response protein (CIRBP) that alters the translational efficiency of its target messenger RNAs (mRNAs). This review summarizes recent work on the roles of CIRP in the context of inflammation and cancer. The function of CIRP in cancer appeared to be solely driven though its functions as an RBP that targeted cancer-associated mRNAs, but it is increasingly clear that CIRP also modulates inflammation. Several recent studies highlight roles for CIRP in immune responses, ranging from sepsis to wound healing and tumor-promoting inflammation. While modulating inflammation is an established role for RBPs that target cytokine mRNAs, CIRP appears to modulate inflammation by several different mechanisms. CIRP has been found in serum, where it binds the TLR4-MD2 complex, acting as a Damage-associated molecular pattern (DAMP). CIRP activates the NF-κB pathway, increasing phosphorylation of Iκκ and IκBα, and stabilizes mRNAs encoding pro-inflammatory cytokines. While CIRP promotes higher levels of pro-inflammatory cytokines in certain cancers, it also decreases inflammation to accelerate wound healing. This dichotomy suggests that the influence of CIRP on inflammation is context dependent and highlights the importance of detailing the mechanisms by which CIRP modulates inflammation. WIREs RNA 2018, 9:e1462. doi: 10.1002/wrna.1462 This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.

Keywords: A18 hnRNP; CIRP; RNA binding protein; cancer; inflammation; stress.

Figure 1

CIRP as a Tumor Suppressor. CIRP moves from the nucleus to the cytoplasm in response to stress such as DNA damage and cold-stress. In the cytoplasm, CIRP binds the 3′UTR of mRNAs encoding ATR, Trx-1 and RPA2, and interacts with eIF4G to increase translational efficiency of these mRNAs. The end result is inhibition of proliferation. In response to cold-stress, CIRP slows G1 phase of the cell cycle by an unknown mechanism. Red dashed arrows indicate potential links to suggested CIRP functions

Figure 2

Roles of CIRP as a tumor promoter. CIRP moves from the nucleoplasm into Cajal bodies where it stabilizes hTERC and telomerase complex assembly via protein-protein interaction. CIRP also moves from the nucleus to the cytoplasm where it binds and stabilizes cyclin E1 mRNA, and binds hTERT mRNA, increasing both of these proteins. CIRP also downregulates p53 and upregulates EMT markers, cyclin D1, 4E-BP1, S6 and ERK1/2 by unknown mechanisms. The overall result is increased cell proliferation and cell survival. Arrows and boxes in black represent known roles from literature and red dashed arrows and boxes represent possible mechanisms or connections.

Figure 3

Roles of CIRP as a mediator of inflammation. In response to cold-stress CIRP stimulates mucus secretion, inflammation and tissue damage in the lung. In response to DNA damage, CIRP decreases TNFα to promote wound healing and increases IL1β, IL-8 and TNFα in neurons as well as inducing apoptosis and neural tissue damage. Also in response to DNA damage, CIRP is found extracellularly where it binds MD2 in TLR-4 complexes of professional antigen presenting cells (APC) and splenic T-cells. This results in cytokine release and T-cell activation. and Red dashed arrows indicate potential links to suggested CIRP functions. Arrows and boxes in black represent known roles from literature and red dashed arrows and boxes represent possible mechanisms or connections.

Figure 4

Summary of CIRP Roles in Inflammation and Cancer. CIRP shuttles from the nucleus to the cytoplasm to bind the 3′ UTRs of target mRNA to increase their translation. It is possible that CIRP can bind tumor promoting cytokines in certain contexts. CIRP in found extracellularly in patients with sepsis (likely through lysosomal secretion) where it binds the TLR-4 MD2 complex, functioning as a DAMP and stimulating cytokine release from APCs. Also, CIRP increases Iκκ phosphorylation through an unknown mechanism. Arrows and boxes in black represent known roles from literature and red dashed arrows and boxes represent possible mechanisms or connections.