Related Experiment Video

Updated: Jul 10, 2025

Monitoring Activation of the Antiviral Pattern Recognition Receptors RIG-I And PKR By Limited Protease Digestion and Native PAGE
12:43

Monitoring Activation of the Antiviral Pattern Recognition Receptors RIG-I And PKR By Limited Protease Digestion and Native PAGE

Published on: July 29, 2014

12.2K

SARS-CoV-2 ORF6 protein targets TRIM25 for proteasomal degradation to diminish K63-linked RIG-I ubiquitination and

Oyahida Khatun1,2, Mansi Sharma1,2, Rohan Narayan1,2

  • 1Emerging Viral Pathogens Laboratory, Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru, India.

Cellular and Molecular Life Sciences : CMLS
|November 20, 2023
PubMed

Insights

The SARS-CoV-2 ORF6 protein inhibits the host

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • SARS-CoV-2 evades host immunity, aiding viral replication and COVID-19.
  • Type-I Interferons (IFNs) are crucial for innate immune defense against viral infections.

Purpose of the Study:

  • To investigate the role of SARS-CoV-2 proteins in antagonizing host innate immunity.
  • To elucidate the specific mechanism by which ORF6 protein inhibits type-I IFN induction and signaling.

Main Methods:

  • Exploration of SARS-CoV-2 protein interactions with host immune components.
  • Analysis of Interferon Regulatory Factor 3 (IRF3) and Signal Transducer and Activator of Transcription 1 (STAT1) nuclear import.
  • Investigation of ORF6 interaction with RIG-I and its ubiquitination status.
  • Mapping of ORF6's type-I IFN antagonistic activity to its C-terminal tail.

Main Results:

  • SARS-CoV-2 ORF6 protein mitigates type-I Interferon (IFN) induction and signaling.
  • ORF6 blocks IRF3 and STAT1 nuclear import, inhibiting IFN pathways.
  • ORF6 directly interacts with RIG-I, reducing K63-linked ubiquitination and downstream IFN induction.
  • ORF6 targets E3 ligase TRIM25 for proteasomal degradation, a process observed during SARS-CoV-2 infection.
  • The C-terminal cytoplasmic tail of ORF6 (residues 52-61) is responsible for type-I IFN antagonism.

Conclusions:

  • SARS-CoV-2 ORF6 protein is a key viral factor that antagonizes the host's type-I IFN response.
  • ORF6 employs multiple strategies, including RIG-I ubiquitination disruption and TRIM25 degradation, to inhibit IFN induction and signaling.
  • Understanding ORF6's mechanism provides insights into SARS-CoV-2 pathogenesis and potential therapeutic targets.
Keywords:
ORF6RIG-ISARS-CoV-2TRIM25Type-I IFNUbiquitination

More Related Videos

A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF311:44

A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3

Published on: January 24, 2016

12.0K
Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy08:51

Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy

Published on: April 3, 2018

9.1K

Related Concept Videos

siRNA - Small Interfering RNAs02:30

siRNA - Small Interfering RNAs

Small interfering RNAs, or siRNAs, are short regulatory RNA molecules that can silence genes post-transcriptionally, as well as the transcriptional level in some cases. siRNAs are important for protecting cells against viral infections and silencing transposable genetic elements.
In the cytoplasm, siRNA is processed from a double-stranded RNA, which comes from either endogenous DNA transcription or exogenous sources like a virus. This double-stranded RNA is then cleaved by the...
16.8K
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.4K
Experimental RNAi02:15

Experimental RNAi

RNA interference (RNAi) is a cellular mechanism that inhibits gene expression by suppressing its transcription or activating the RNA degradation process. The mechanism was discovered by Andrew Fire and Craig Mello in 1998 in plants. Today, it is observed in almost all eukaryotes, including protozoa, flies, nematodes, insects, parasites, and mammals. This precise cellular mechanism of gene silencing has been developed into a technique that provides an efficient way to identify and determine the...
6.1K
The Unfolded Protein Response01:37

The Unfolded Protein Response

The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
4.7K
RNA Interference01:23

RNA Interference

RNA interference (RNAi) is a process in which a small non-coding RNA molecule blocks the post-transcriptional expression of a gene by binding to its messenger RNA (mRNA) and preventing the protein from being translated.
This process occurs naturally in cells, often through the activity of genomically-encoded microRNAs. Researchers can take advantage of this mechanism by introducing synthetic RNAs to deactivate specific genes for research or therapeutic purposes. For example, RNAi could be used...
26.1K
Leaky Scanning02:28

Leaky Scanning

During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA.  Marilyn Kozak discovered that the sequence RCCAUGG (where R...
5.1K