Unique effects of retroviruses on cap-dependent translation and protein trafficking
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The tight regulation of protein expression is critical for the survival of mammalian cells, providing a vital line of defense against viral attacks. Since translation initiation is the rate limiting step of translation, viruses have evolved various mechanisms to efficiently subvert translation initiation for their own advantage. Here I present a unique and previously unrecognized system of host translational regulation utilized by vectors containing retroviral sequences. I found that introduction into mammalian cells of specific viral DNA vectors increased host translation through a novel cap-dependent translation initiation mechanism, which is different from the canonical cap-dependent translation regulated by mTORC1 signaling1. These viral DNA vectors specifically enhanced exogenous protein translation efficiency of capped mRNA expressed from unrelated vectors in trans, a result opposite from the typical type I interferon response to detection of viral nucleic acids. Since protein expression efficiency of a specific exogenous protein in different mammalian cells can be increased by the introduction of these viral DNA vectors with minor modifications, this observation has the potential for application to basic research as well as production of protein-based drugs, such as antibodies or interferon, DNA vaccines, and gene therapy. Studies of retroviruses also resulted in another interesting discovery. Previous studies of mouse mammary tumor virus (MMTV have shown that the MMTV-encoded Rem is a precursor that is cleaved by signal peptidase in the endoplasmic reticulum (ER), where the N-terminal signal peptide (Rem-SP) subverts the ER-associated degradation (ERAD) pathway. Deregulation of the ERAD process plays a crucial role in several human diseases, including Alzheimer’s disease, Parkinson’s disease, cancer, and cystic fibrosis. My studies focused on the Rem C-terminus (Rem-CT) whose function is largely unknown. Surprisingly, I found that Rem-CT as well as Rem-SP were able to utilize the ERAD pathway. A portion of Rem-CT utilizes the cellular vesicle trafficking pathway to traffic out of the ER, yet then uses Arf1 to return to the ER for retrotranslocation and ERAD. Further study of the mechanism of Rem-CT trafficking and function will shed light on how viruses manipulate cellular systems to promote virus replication.