The Multiple Functions of TRBP, at the Hub of Cell Responses to Viruses, Stress, and Cancer

Abstract

SUMMARY The TAR RNA binding protein (TRBP) has emerged as a key player in many cellular processes. First identified as a cellular protein that facilitates the replication of human immunodeficiency virus, TRBP has since been shown to inhibit the activation of protein kinase R (PKR), a protein involved in innate immune responses and the cellular response to stress. It also binds to the PKR activator PACT and regulates its function. TRBP also contributes to RNA interference as an integral part of the minimal RNA-induced silencing complex with Dicer and Argonaute proteins. Due to its multiple functions in the cell, TRBP is involved in oncogenesis when its sequence is mutated or its expression is deregulated. The depletion or overexpression of TRBP results in malignancy, suggesting that the balance of TRBP expression is key to normal cellular function. These studies show that TRBP is multifunctional and mediates cross talk between different pathways. Its activities at the molecular level impact the cellular function from normal development to cancer and the response to infections.

HIV-1 RRE RNA acts as an RNA silencing suppressor by competing with TRBP-bound siRNAs

“…4 TAR has been suggested to suppress RNAi by sequestering TRBP, which may prevent its interaction with Dicer. 33 To evaluate whether RRE may act in a similar manner, we first examined whether RRE was also able to bind to TRBP.…”

“…16,32 TAR has been proposed to disrupt RNAi activity by binding TRBP, thereby sequestering it from the RISC. 33 TRBP has been shown to be a crucial, nonredundant component of RNAi, 4,34 so its removal from the RISC would be highly detrimental to RNAi function. However, knockdown of TRBP decreases HIV-1 replication, suggesting that either RNAi does not restrict HIV-1 RNA or that TRBP has other crucial functions for the virus independent of RNAi.…”

“…2 Pre-miRNAs are then exported into the cytoplasm via an exportin-5 mediated pathway, where they are bound by Dicer and the TAR-RNA-Binding Protein (TRBP). [3][4][5][6][7] These 2 proteins process pre-miRNAs into mature double-stranded (ds) miRNAs. The active strand of this mature miRNA is retained in the Dicer-TRBP complex, which then recruits the endonuclease Argonaute-2 (Ago2).…”

Trans-activation Response (TAR) RNA-binding Protein 2 Is a Novel Modulator of Transient Receptor Potential Canonical 4 (TRPC4) Protein

“…1C). Their overlapping DNA encodes aa 93-274 and, thus, about 50% of the Tarbp2 protein, including the doublestranded RNA-binding domain (dsRBD) 2, followed by a sequence that has been implicated in protein-protein interaction (19). Clones from colonies that exhibited galactose-dependent growth at 37°C were verified by retransformation (Fig.…”

“…Our experiments focused on the identification of components of TRPC4 channels. Tarbp2, or TRBP2 (18,19), which was one of the first proteins involved in the identification of double-stranded RNA-binding proteins and which, in mammals, is part of the RNA-induced silencing complex, including Argonaute and Dicer (20 -23), was found to interact with TRPC4 and TRPC5 and to modulate receptor-activated, TRPC4-dependent Ca 2ϩ entry as well as constitutive Ca 2ϩ entry accomplished by TRPC4 and TRPC5 gain-of-function channel mutants. In addition, Dicer activity is shown to be increased in the presence of Ca 2ϩ , most probably by Ca 2ϩ -dependent proteolytic activation of the enzyme.…”