Completed Cells, Biochemistry & Physiology Infection & Immunity

The control of MHC class I by viral and cellular E3 ligases.

Funder Wellcome Charity-funded
Recipient organisation University of Cambridge
Funding £1.7M
Period Aug 2008 — Jul 2013

In plain English

AI plain-English summary

Viruses use molecular “scissors” to snip immune receptors off the surface of infected cells, and this project aims to find out exactly how they do it. The immune system relies on proteins called MHC class I molecules, which sit on cell surfaces and flag infections for destruction. Some viruses, such as herpesviruses, produce enzymes—E3 ligases—that tag these molecules with ubiquitin, marking them for degradation inside the cell. This allows the virus to hide from immune detection. The researchers have already shown that a specific type of ubiquitin chain (linked at lysine-63) is essential for this process. They now want to identify the human cellular E3 ligase that normally controls MHC class I levels, and which the viral enzymes hijack. They will use biochemical inhibitors and RNA interference screens to find it. This is fundamental science. It asks how cells regulate key immune receptors, and how viruses subvert that regulation. If successful, it could reveal new drug targets for autoimmune diseases—where immune receptors are overactive—or for infections where viruses evade immunity. The work also uncovered a new family of human enzymes, the MARCH proteins, which may regulate many other surface receptors. Understanding their normal roles could eventually inform therapies for cancer, inflammation, or transplant rejection, though that is years away.

View original technical description
Regulation of cell surface receptors is essential to maintain cell homeostasis, especially following receptor stimulation to limit the duration and intensity of signalling. Receptor ubiquitination is an important mechanism for regulating expression of critical immunoreceptors. The K3 and K5 viral E3 ligases ubiquitinate cell surface class I, promoting its endolysosomal degradation, and we showed an absolute requirement for lysine-63 linked polyubiquitination of class I for its downregulation. Th ese viral genes accelerate a constitutive pathway of class I regulation. Continued studies on K3 and K5 will further define this receptor regulation pathway. Biochemical inhibitors of class I ubiquitination, and RNAi screens will identify the cellular ligase(s) responsible for class I ubiquitination, and establish the role of lysine-63 linked polyubiquitination in regulating class I and other immunoreceptors. Investigations into the viral ligases identified an unrecognised family of cellular lig ases the MARCH proteins, whose expression downregulates surface receptors. We have developed screening and mass spectrometry-based techniques, as well as MARCH9 knockout mice, to identify the substrates and function of these proteins. Biochemical studies on the regulation and expression of MARCH9, together with an analysis of MARCH9 deficient mice will determine the physiological role of the MARCH9 E3 ligase in immunoreceptor regulation.

View the original record at the funder ↗

Researchers

Paul Lehner (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

The role of MARCH1 in the ubiquitination and regulation of surface immunoreceptors
Posttranslational control of our innate immune response: exploring a novel role for ISGylation.
Viral and endogenous regulation of cellular immunoreceptors.
Ubiquitin Signalling
Elucidating the regulation of Rsp5 a paradigm for the Nedd4-family of ubiquitin ligase proteins

Original classification

Senior Research Fellowship Clinical Renewal

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