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AssigneeThe Board of Trustees of the Leland Stanford Junior University
InventorsC. Garrison Fathman, Luis Soares
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An active ubiquitin E3 ligase, GRAIL, is crucial in the induction of anergy in cells of the immune system, and in the regulation of cellular proliferation. GRAIL is shown to associate with, and be regulated by Otubain isoforms, including OTUBAIN-1 (DOG, the Destabilizer of GRAIL) and an alternative reading frame splice variant of OTUBAIN-1 (SOG, the Stabilizer of GRAIL). These proteins play opposing roles in the regulation of GRAIL auto-ubiquitination and consequently on its ability to induce anergy and regulate cellular proliferation. DOG serves as an adaptor protein, recruiting the DUB USP8. One major substrate for USP8 is the Ras exchange factor Ras-GRF1, and this protein can be found in a complex with USP8 and GRAIL, which complex is ubiquitinated by GRAIL.
A method for identifying an agent that modulates activity of the GRAIL complex in a cell, the method comprising:
A method of determining the substrates of an E3 ligase, the method comprising:
An animal model for biological function of the GRAIL complex, comprising:
A method of treating a proliferative disorder, said method comprising:
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An isolated polypeptide complex comprising GRAIL and one or more of an otubain isoform;
A method of diagnosing a defect in immune tolerance or cellular proliferation, the method comprising determining the steady state level of GRAIL polypeptide or an otubain isoform polypeptide, wherein an alteration compared to a normally tolerant control cell is indicative of a defect in tolerance or cellular proliferation.
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Dependencies are inferred from the claim text.