Chaperone Directs mRNA Stability

Science's STKE  23 Jan 2007:
Vol. 2007, Issue 370, pp. tw29
DOI: 10.1126/stke.3702007tw29

Heat-shock cognate protein 70 (HSC70) is a multifunctional protein that has known functions as an adenosine triphosphatase (ATPase) in the uncoating of clathrin-coated vesicles and in the facilitation of protein folding. Matsui et al. provide evidence that this versatile protein also serves to regulate stability of the mRNA encoding the proapoptotic protein Bim. During hematopoiesis, survival of the hematopoietic progenitor cells is determined, at least in part, by cytokines that decrease the abundance of Bim. Treatment of cultured Baf-3 cells with interleukin-3 (IL-3) caused destabilization of Bim mRNA. To explore the mechanism behind this effect, the authors analyzed proteins that interacted with the 3′ untranslated region (UTR) of Bim mRNA during affinity chromatography. Matrix-assisted laser desorption/ionization–time-of-flight (MALDI-TOF)/TOF mass spectrometry revealed the association of HSC70 with the Bim 3′-UTR, and this association was decreased in cells treated with IL-3. In IL-3-treated cells, HSC70 was associated with the cochaperones Bag-4 and CHIP, whereas in IL-3-starved cells, two other cochaperones, Hsp40 and Hip, were the more prevalent partners of HSC70. Survival signals from cytokine receptors are thought to be carried by pathways activated by the small guanosine triphosphatase Ras, and cells expressing constitutively active Ras showed rapid loss of Bim mRNA. The authors propose a model in which cells exposed to a survival signal from IL-3 have HSC70 protein associated with its cochaperones Bag-4 and CHIP, with little potential to bind RNA. Under these conditions, Bim mRNA tends to interact with RNA-destabilizing factors. However, if IL-3 is removed, signals not yet resolved cause HSC70 to interact preferentially with Hsp40 and Hip. Interaction of this protein complex with Bim mRNA appears to protect the Bim mRNA from degradation. The authors also point out that these hematopoietic processes are disturbed in leukemia; thus, understanding the regulatory mechanisms involved may offer new strategies for disease intervention.

H. Matsui, H. Asou, T. Inaba, Cytokines direct the regulation of Bim mRNA stability by heat-shock cognate protein 70. Mol. Cell 25, 99-112 (2007). [Online Journal]