Unique trafficking of mouse mammary tumor virus rem protein and its effects on ERAD and adaptive immunity

Abstract

Protein quality control is of the utmost importance within the cell. Misfolded proteins and misassembled protein complexes lead to protein aggregates that have been associated with disease states such as Alzheimer’s, Parkinson’s, and cancer. Studies of the retrovirus MMTV have revealed a novel protein, Rem, with a unique trafficking scheme that subverts host endoplasmic reticulum-associated degradation (ERAD). At least a third of cellular proteins are synthesized in association with the ER and mishaps in ERAD further contribute to the formation of disease-associated protein aggregates. Utilizing a novel protein technology, ubiquitin- activated interaction traps or UBAITs, additional evidence for a novel, p97-dependent, Derlin- independent ERAD mechanism has been attained. These studies have potential application for manipulation of ERAD and protein quality control for therapeutic and anti-viral benefits. Additional studies of Rem have revealed a possible antagonistic function on the adaptive immune system. AID is the enzyme responsible for somatic hypermutation and class switch recombination at immunoglobulin loci in activated B cells. Studies in our lab have shown that RemCT, a cleaved product of Rem with a unique trafficking scheme, results in degradation AID in cell culture. Further, the lack of RemCT in virally-infected mice leads to the accumulation of AID-like mutations within proviral sequences from MMTV-induced mammary and T-cell tumors. Here I present a novel screen utilizing the new UBAIT technology, which identified a direct interaction between MMTV-encoded SP and the ERAD component, p97. The UBAIT strategy also suggested host proteins affecting AID stability in the presence and absence of the Rem C-terminus.