Discovery of a novel regulatory protein involved in regulating the innate immune response

Researchers from Sanford Burnham Prebys Medical Discovery Institute (SBP) (La Jolla, CA, USA) have discovered a novel protein, which appears to modulate the innate immune response, termed K-homology splicing regulatory protein (KHSRP).

The study, recently published in Nature Microbiology, provides a new potential target for future antiviral therapies, as well as treatments for cancer and autoimmune diseases.

The innate immune response is a tightly regulated process activated when pathogens such as viruses and bacteria are detected in the body. “That’s where KHSRP comes in. It physically interacts with a protein called retinoic acid-inducible gene I (RIG-I) to apply the brakes to the innate immune response,” explained author Sumit Chanda, Director of the Immunity and Pathogenesis Program (SBP).

RIG-l receptors are activated upon binding with viral RNA and are not only responsible for initiating antiviral immunity but also the adaptive immune response.

For this reason Chandra and his colleagues systematically tested every human protein that influenced RIG-I signaling. Out of 240 proteins identified, KHSRP was the only one that inhibited the early steps of RIG-l signaling.

Following this, the team investigated the effects of KHSRP inhibition on the immune response in cell culture and in vivo. Their results demonstrated that depleting KHSRP improved immune signaling and reduced viral replication, indicating the therapeutic potential of KHSRP inhibitors.

First author Stephen Soonthornvacharin (SBP) commented: “Molecules that block KHSRP’s actions could serve as adjuvants – components that heighten the immune response – to vaccines against influenza or hepatitis C, as antiviral drugs, or even next-generation cancer immunotherapies.”

“Also, among the 240 RIG-I regulators we identified, 125 appear to activate RIG-I, so finding drugs that inhibit these proteins may be a way to treat autoimmune conditions involving too much interferon, like type 1 diabetes or lupus.”

Sunnie Yoh, an author of the study (SBP), added: “Next, we plan to figure out more of the details of how KHSRP regulates RIG-I. That’s the information that will move us in the direction of developing therapies.”

Sources: Soonthornvacharin S, Rodriguez-Frandsen A, Zhou Yet al. Systems-based analysis of RIG-I-dependent signalling identifies KHSRP as an inhibitor of RIG-I receptor activation. Nat. Microbiol. doi:10.1038/nmicrobiol.2017.22 (Epub ahead of print)


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