A60
Ataxia telangiectasia mutated(ATM) is required for the interferon-γ response
Diane Watling1, Catarina R. Carmo1, Ian M. Kerr2, Ana P. Costa-Pereira1
1Imperial College London, London, UK, 2Cancer Research UK - London research Institute, London, UK
Interferons (IFNs) are essential to the control of infection and the immune response, and manifest tumour suppressor function(s). IFN-gupregulates Class II HLA expression on most cell types rendering them visible to CD4+ T cells. A defect in the IFN-ginducibility of Class II HLA is a common feature of human tumour cells of potential importance in the evasion of immune surveillance. Activation of Janus kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs) is essential but not sufficient for a full IFN-gresponse. Additional signalling pathways are activated but much remains to be understood regarding their significance and function. A powerful, robust FACS-based quantitative short-interfering RNA (siRNA) screen has identified nine kinases as likely required for the IFN-γClass II HLA response, seven for an antiviral response and two for the cytopathic response to encephalomyocarditis virus (EMCV). More particularly, ataxia telangiectasia-mutated (ATM) was shown to be phosphorylated in response to IFN-γ. Inhibition of the IFN-γresponse by siATM differentially affects a spectrum of IFN-γ-stimulated mRNAs, with inhibitions being seen as early as one hour (CIS and SOCS1 mRNAs) and six hours (CIITA mRNA) post-stimulation. This unexpected implication of ATM potentially links IFN-gaction with the DNA damage response. More generally, the work reveals previously unrecognised requirements for ATM and eight additional kinases, dissection of the mechanistic requirements for which will expose novel aspects of cytokine action to further investigation and suggest additional targets for clinical intervention.
