Cold-Inducible RNA-Binding Protein Mechanisms in Cellular Responses

Cold-inducible RNA-binding proteins, principally CIRP and RBM3, are evolutionarily conserved sensors of sub-physiological temperature. Upon exposure to cold or hypoxic stress, these proteins undergo rapid transcriptional upregulation and nucleocytoplasmic redistribution, engaging target transcripts via RNA-recognition motifs. By binding to 3′-untranslated regions, they modulate mRNA stability, translation efficiency and microRNA biogenesis. Their activity orchestrates broad adaptive programmes including cell survival, circadian regulation, synaptic plasticity and anti-apoptotic pathways. In neural and renal tissues, their induction attenuates ischaemia-reperfusion injury and promotes neurogenesis, while extracellular release of CIRP can amplify inflammatory signalling. Emerging research illuminates their mechanistic interplay with key factors such as HIF-1α, IMP2–IGF2 and ATM/ATR kinases, underscoring their potential as therapeutic targets in hypothermic medicine, neuroprotection and inflammatory disorders.

Research from Nature Portfolio

An investigation into post-injury neurogenesis has revealed that RBM3, induced by therapeutic hypothermia, drives neuronal differentiation via a novel IMP2–IGF2 axis. This study demonstrates that RBM3 upregulation in the subgranular zone enhances neural stem/progenitor proliferation and reduces apoptosis in hypoxic-ischaemic models, unveiling a niche-dependent signalling pathway. By elevating IGF2 release through IMP2 interaction, RBM3 confers sustained functional recovery and offers insight into temperature-mediated modulation of adult neurogenesis.

Cold-Inducible RNA-Binding Protein Mechanisms in Cellular Responses publication trend

The graph below shows the total number of articles in cold-inducible rna-binding protein mechanisms in cellular responses across all publications each year (not limited to Nature Index journals).

Technical terms

Cold-Inducible RNA-Binding Protein (CIRP): A stress-responsive RBP upregulated by low temperature and hypoxia, modulating mRNA stability and stress pathways.

RNA-Binding Motif Protein 3 (RBM3): A cold shock protein that binds to RNA, promotes translation and supports cell survival under hypothermic stress.

Cold shock protein: A class of proteins induced by temperature downshift that protect cells by stabilising transcripts and regulating translation.

Hypothermia: Controlled or pathophysiological reduction of core temperature used to trigger protective molecular responses.

3′-Untranslated Region (3′-UTR): A non-coding segment of mRNA crucial for post-transcriptional regulation by RNA-binding proteins.

References

1. Cold-inducible proteins CIRP and RBM3, a unique couple with activities far beyond the cold. Cellular and Molecular Life Sciences (2016).
2. Widespread Regulation of miRNA Biogenesis at the Dicer Step by the Cold-Inducible RNA-Binding Protein, RBM3. PLOS ONE (2011).
3. RBM3 promotes neurogenesis in a niche-dependent manner via IMP2-IGF2 signaling pathway after hypoxic-ischemic brain injury. Nature Communications (2019).
4. CIRP attenuates acute kidney injury after hypothermic cardiovascular surgery by inhibiting PHD3/HIF-1α-mediated ROS-TGF-β1/p38 MAPK activation and mitochondrial apoptotic pathways. Molecular Medicine (2023).
5. Mild and deep hypothermia differentially affect cerebral neuroinflammatory and cold shock response following cardiopulmonary bypass in rat. Brain Behavior and Immunity (2024).
6. Decreased cold‐inducible RNA‐binding protein (CIRP) binding to GluRl on neuronal membranes mediates memory impairment resulting from prolonged hypobaric hypoxia exposure. CNS Neuroscience & Therapeutics (2024).