MHC-1
Many viruses decrease cell surface MHC I expression
Viral gene products utilise ubiquitin to inhibit MHC-I pathway
Viral Evaion of the Human Immune system: Viral and endogenous regulation of MHC-I antigen presentation pathways
Viruses antagonise host defence pathways to enable their escape from immune detection. Our interest in this area was initiated by showing how herpesviruses inhibit MHC antigen presentation, revealing new intracellular signalling pathways. Together with Phil Stevenson, we discovered a family of Kaposi’s sarcoma associated herpesvirus derived immune-evasion proteins (The K3 and K5 family) and showed that they are virally-encoded ubiquitin E3 ligases8. We found that viral ubiquitination of MHC-I with non-canonical lysine-63 linked ubiquitin chains, as opposed to canonical lysine-48 linked chains, initiate degradation in lysosomes, as opposed to the proteasome. The realisation that lysine-63 ubiquitin chains direct their substrate to a different cellular compartment, established a paradigm for ubiquitin-dependent, endolysosomal regulation of cell surface receptors. This work challenged the prevailing view that in vivo ubiquitin chain-linkages are homotypic (single lysine linkage) and established a now well-recognised, role for mixed-linkage ‘heterotypic’ ubiquitin chains in intracellular signalling and protein trafficking.
References
Duncan, LM, Piper, S, Dodd, RB, Saville, MK, Sanderson, CM, Luzio JP and Lehner PJ. Lysine-63 Linked Ubiquitination Is Required For Endolysosomal Degradation of Class I Molecules. EMBO Journal (2006) 25:1635-1645. PMID: 16601694 doi: 10.1038/sj.emboj.7601056
Boname JM, Thomas M, Stagg HR, Xu P, Peng J, Lehner PJ. Efficient Internalization of MHC I Requires Lysine-11 and Lysine-63 Mixed Linkage Polyubiquitin Chains. Traffic (2010) 210 – 220 PMID: 19948006 doi: 10.1111/j.1600-0854.2009.01011.x.
Stagg, HR, Thomas M, Van den Boomen D, Wiertz EH, Drabkin HA, Gemmill RM and Lehner PJ. The TRC8 E3 Ligase ubiquitinates MHC class I molecules before dislocation from the ER. Journal of Cell Biology (2009) 186(5):685-92 PMID: 19720873 doi: 10.1083/jcb.200906110.
Van den Boomen DJH, Timms RT, Grice G, Stagg HR Skødt HR, Dougan G, Nathan JA & Lehner PJ. TMEM129 is a Derlin-1 associated ERAD E3 ligase essential for virus-induced degradation of MHC-I. Proc Natl Acad Sci (2014) 11(31):11425-30 PMID: 25030448 doi: 10.1073/pnas.1409099111.
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 (2011) 108:2034-9 PMID: 21245296. doi: 10.1073/pnas.1016229108.
Ongoing work in this area:
Regulation of MHC class I in specialized tissues. For example we are interested in the regulation of HLA-G on the surface of placental extra-villous trophoblast cells and how this may be linked to trophoblast differentiation (See work of Alex Griffiths)
Using genetic approaches e.g. Genome-wide, or subgenomic targeted CRISPR screens to identify novel pathways inhibited by viruses