Shiftless Is a Novel Member of the Ribosome Stress Surveillance Machinery That Has Evolved to Play a Role in Innate Immunity and Cancer Surveillance

Abstract

A longstanding paradox in molecular biology has centered on the question of how very long proteins are synthesized, despite numerous measurements indicating that ribosomes spontaneously shift reading frame at rates that should preclude their ability completely translate their mRNAs. Shiftless (SFL; C19orf66) was originally identified as an interferon responsive gene encoding an antiviral protein, indicating that it is part of the innate immune response. This activity is due to its ability to bind ribosomes that have been programmed by viral sequence elements to shift reading frame. Curiously, Shiftless is constitutively expressed at low levels in mammalian cells. This study examines the effects of altering Shiftless homeostasis, revealing how it may be used by higher eukaryotes to identify and remove spontaneously frameshifted ribosomes, resolving the apparent limitation on protein length. Data also indicate that Shiftless plays a novel role in the ribosome-associated quality control program. A model is proposed wherein SFL recognizes and arrests frameshifted ribosomes, and depending on SFL protein concentrations, either leads to removal of frameshifted ribosomes while leaving mRNAs intact, or to mRNA degradation. We propose that SFL be added to the growing pantheon of proteins involved in surveilling translational fidelity and controlling gene expression in higher eukaryotes.

The Inhibition of Gag-Pol Expression by the Restriction Factor Shiftless Is Dispensable for the Restriction of HIV-1 Infection

“…Finally, our study suggests that SFL can interfere with HIV-1 infection without inhibiting −1PRF. Recent work by the Dinman group has shown that SFL overexpression leads to a reduction in mRNA abundance of both reporter and endogenous cellular mRNAs [ 51 ]. It is conceivable that the various SFL mutants that we have analyzed could impact gag-pol mRNA levels in a different way, possibly due to variable extents of mRNA binding or recruitment of mRNA surveillance proteins.…”

Interferon-Stimulated Genes that Target Retrovirus Translation

“…However, other modes of action are possible, including interference with the expression of other viral proteins, such as Env. Furthermore, a recent study has shown that both SFL overexpression and depletion can reduce the abundance of reporter mRNAs, independent of whether they possess an FSE [ 128 ]. Although it is important to note that this study was carried out with frameshift reporter systems rather than with authentic viruses [ 128 ], this finding may suggest that SFL plays a role in modulating RNA stability and might be involved in cellular RNA decay pathways, as described in the context of other viral infections [ 97 , 99 ].…”