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Cambridge Immunology Network



Regulated degradation of mRNAs is important as it allows cells to continually adjust their gene expression programme to their current needs. How mRNA degradation is regulated, however, remains poorly understood. We have recently discovered a link between ubiquitin and the modulation of mRNA decay, through the action of RNA-binding E3 ubiquitin ligases.

My work focuses on understanding the relevance of these RNA-binding E3 ligases in different aspects of immune processes. In particular I study the role of MEX-3C, a novel RNA-binding E3 ligase, in the regulation of MHC class I (MHC-I) mRNA decay through its ubiquitin ligase activity. In an siRNA ubiquitome screen I identified a previously unrecognised function for MEX-3C as an RNA-binding protein with ubiquitin E3 ligase activity, that, post-transcriptionally mediates MHC-I mRNA decay. In human cells, MEX-3C binds the 3’UTR of HLA-A2 (an MHC-I allotype) mRNA and represses HLA-A2 translation in a RING-independent manner. Most importantly, MEX-3C induces HLA-A2 mRNA degradation in a RING-dependent manner.

MEX-3C is highly expressed in cells of the immune system, in particular NK cells. Its expression increases upon NK cell activation as will occur when these cells enter an inflammatory environment. Increased MEX-3C expression decreases cell surface HLA-A levels and lowers the threshold for cytotoxic killing by these cells. It is likely that MEX-3C binds and regulates additional mRNA species. The identification of new mRNA targets will provide further insight into the function and physiological role of this novel E3 ligase, and possibly the whole family of RNA-binding E3 ligases.


Key publications: 

Cano F, and Lehner PJ. A novel post-transcriptional role for ubiquitin in the differential regulation of MHC class I allotypes. Mol Immunol. 2013 Sep;55(2):135-8.

Cano F, Bye H, Duncan LM, Buchet-Poyau K, Billaud M, Wills M, Lehner PJ. The RNA-binding E3 ubiquitin ligase MEX-3C links ubiquitination with MHC-I mRNA degradation. EMBO J. 2012 Aug 3; 31(17):3596-606. (PubMed ID: 22863774).

Duncan LM, Timms RT, Zavodszky E, Cano F, Dougan G, Randow F, Lehner PJ. Fluorescence-based phenotypic selection allows forward genetic screens in haploid human cells. PLOS One 2012; 7(6):e39651.

Burr ML, Cano F, Svobodova S, Boyle LH, Boname JM, Lehner PJ. HRD1 and UBE2J1 target misfolded MHC class I heavy chains for endoplasmic reticulum-associated degradation. Proc Natl Acad Sci U S A. 2011 Feb 1; 108(5):2034-9.

Cano F, Miranda-Saavedra D, Lehner PJ. RNA-binding E3 ubiquitin ligases: novel players in nucleic acid regulation. Biochem Soc Trans. 2010 Dec; 38(6):1621-6.

Not available for consultancy


Person keywords: 
antigen presentation
MHC class I
RNA binding proteins
mRNA decay
ubiquitin E3 ligase
3′ UTR
NK cells