Cold shock proteins: from cellular mechanisms to pathophysiology and disease

Abstract

Cold shock proteins are multifunctional RNA/DNA binding proteins, characterized by the presence of one or more cold shock domains. In humans, the best characterized members of this family are denoted Y-box binding proteins, such as Y-box binding protein-1 (YB-1). Biological activities range from the regulation of transcription, splicing and translation, to the orchestration of exosomal RNA content. Indeed, the secretion of YB-1 from cells via exosomes has opened the door to further potent activities. Evidence links a skewed cold shock protein expression pattern with cancer and inflammatory diseases. In this review the evidence for a causative involvement of cold shock proteins in disease development and progression is summarized. Furthermore, the potential application of cold shock proteins for diagnostics and as targets for therapy is elucidated.

Fig. 1

The human cold shock domain proteins. The five groups of human cold shock proteins are presented. The number of proteins in each group is indicated within the brackets. The cold shock domain (CSD) is presented in blue. Lin28 contains two additional zinc finger domains (grey bars). The numbers below indicate the approximate number of amino acids. Structure predictions were performed using the SMART software [215]

Fig. 2

Potential amplification loop for YB-1 in inflammation. (1) Extracellular stimuli (e.g. TGF-β, PDGF-B, LPS) activate cells and induce YB-1 secretion. (2) YB-1 binds to specific membrane associated receptors on the cell surface inducing intracellular signaling cascades that result in kinase activation. YB-1 can also be endocytosed. (3) Activated kinases (e.g. Akt/PKB, ERK, JAK2, RSK) phosphorylate cytoplasmic YB-1 (indicated by the yellow circle), inducing its nuclear translocation. (4) In the nucleus, YB-1 activates the transcription of target genes, as well as induces its own expression and that of DbpA. Cold shock proteins are rapidly induced in response to cell stress, due in part to the existence of preformed complexes of cold shock proteins with their cognate mRNA. (5) Activated cells may also secrete YB-1, which may then act in either an autocrine or paracrine manner. Activated cells may also secrete DbpA via the Golgi. (6) Extracellular YB-1 has mitogenic activity that promotes wound healing/fibrosis. YB-1 also contributes to the recruitment of immune cells to the site of inflammation; directly via its chemoattractant activity or indirectly via the products of its target genes, e.g. CCL5/RANTES. Extracellular activities for DbpA await elucidation. Abbreviations: acetylation (Ac); cold shock domain (CSD); DNA binding protein A (DbpA); lipopolysaccharide (LPS); phosphorylation (P); platelet-derived growth factor B homodimer (PDGF-BB); transforming growth factor beta (TGF-β); tumor necrosis factor (TNF); Y-box binding protein 1 (YB-1)