Shiftless: Novel host antiviral factor that inhibits programmed -1 ribosomal frameshifting

January 27, 2019

The genome sizes of viruses are usually relatively small. To increase information content of the genome, many viruses employ a translation recoding mechanism dubbed programmed ribosomal frameshifting.

Translating ribosomes pause at a -1PRF signal. While most ribosomes move on in the original reading frame, a small proportion slip back one nucleotide to translate in a new frame, resulting in two protein products differing at the C-termini. HIV-1 uses programmed -1 ribosomal frameshifting (-1PRF) to produce Gag and Gag-Pol, which are both required for viral replication.

The -1PRF mechanism exists in all domains of life. In eukaryotes, -1PRF may also result in a premature stop codon, which could lead to the degradation of mRNA. The -1PRF mechanism plays an important role in the post-transcriptional regulation of gene expression. However, how -1PRF is regulated by host factors is largely unknown. In a study published in Cell, GAO Guangxia's group at the Institute of Biophysics of the Chinese Academy of Sciences reported a novel host antiviral factor named Shiftless that inhibits -1PRF.

GAO's lab has been focusing on the molecular mechanism underlying virus-host interactions. To identify host factors that inhibit -1PRF, they demonstrated that type I interferon can inhibit the expression of Gag-Pol, the -1PRF product of HIV-1. By screening interferon-stimulated genes (ISG) for their capacity to inhibit Gag-Pol expression, they identified Shiftless (originally named C19orf66).

Shiftless displayed considerable inhibitory activity against all the tested -1PRF from both viruses and cellular genes, indicating that it is a broad-spectrum -1PRF inhibitor.

To explore the mechanism of Shiftless, researchers analyzed the interactions of Shiftless with the -1PRF RNA and translating ribosomes, two key players in the process of -1PRF. Shiftless interacted with both. Based on this result, they reasoned that Shiftless binding to the translating ribosomes and RNA simultaneously might render the ribosome stuck in a non-productive state, stalling on the RNA. The stalled ribosome should be rescued by the quality control mechanism, leading to premature translation termination.

Using a sensitive reporter system, they detected the premature translation termination product, proving their hypothesis. They demonstrated that the premature translation termination was executed by the host translation release factors eRF1 and eRF3.

Moreover, researchers proposed a working model for Shiftless to inhibit -1PRF. Shiftless interacts with the -1PRF signal RNA and the translating ribosome, and thereby causes ribosome stalling at the -1PRF site. Furthermore, Shiftless recruits the translation release factors eRF1-eRF3 to rescue the stalled ribosome, resulting in the production of premature translation termination (PMT) product.

Since -1PRF is a widely used mechanism, these results have far reaching implications that may impact many different fields.

Chinese Academy of Sciences Headquarters

Related RNA Articles from Brightsurf:

A new RNA catalyst from the lab
On the track of evolution: a catalytically active RNA molecule that specifically attaches methyl groups to other RNAs - a research group from the University of Würzburg reports on this new discovery in Nature.

Small RNA as a central player in infections
The most important pathogenicity factors of the gastric pathogen Helicobacter pylori are centrally regulated by a small RNA molecule, NikS.

RNA as a future cure for hereditary diseases
ETH Zurich scientists have developed an RNA molecule that can be used in bone marrow cells to correct genetic errors that affect protein production.

Bringing RNA into genomics
By studying RNA-binding proteins, a research consortium known as ENCODE (Encyclopedia of DNA Elements) has identified genomic sites that appear to code for RNA molecules that influence gene expression.

RNA key in helping stem cells know what to become
If every cell has the same genetic blueprint, why does an eye cell look and act so differently than a brain cell or skin cell?

RNA structures by the thousands
Researchers from Bochum and Münster have developed a new method to determine the structures of all RNA molecules in a bacterial cell at once.

New kind of CRISPR technology to target RNA, including RNA viruses like coronavirus
Researchers in the lab of Neville Sanjana, PhD, at the New York Genome Center and New York University have developed a new kind of CRISPR screen technology to target RNA.

Discovery of entirely new class of RNA caps in bacteria
The group of Dr. Hana Cahová of the Institute of Organic Chemistry and Biochemistry of the CAS, in collaboration with scientists from the Institute of Microbiology of the CAS, has discovered an entirely new class of dinucleoside polyphosphate 5'RNA caps in bacteria and described the function of alarmones and their mechanism of function.

New RNA mapping technique shows how RNA interacts with chromatin in the genome
A group led by scientists from the RIKEN Center for Integrative Medical Sciences (IMS) in Japan have developed a new method, RADICL-seq, which allows scientists to better understand how RNA interacts with the genome through chromatin--the structure in which the genome is organized.

Characterising RNA alterations in cancer
The largest and most comprehensive catalogue of cancer-specific RNA alterations reveals new insights into the cancer genome.

Read More: RNA News and RNA Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to