Scientists have discovered how a key SARS-CoV-2 enzyme can weaken the body’s early antiviral defenses and reorganize the metabolism of infected cells, creating conditions that help the coronavirus multiply. The study focused on the viral papain-like protease, or PLpro, an enzyme contained within the SARS-CoV-2 Nsp3 protein.
Researchers found that PLpro removes protective molecular tags called ISG15 from important human proteins, affecting immune signaling, glucose metabolism, and protection against damaging oxidative stress.
The SARS-CoV-2 uses its PLpro enzyme to remove ISG15 tags from human proteins, weakening innate immunity while reshaping cellular metabolism to favor viral replication.
The researchers involved in the study were from various institutions, including the Florida Research and Innovation Center at Cleveland Clinic and the Department of Microbiology & Immunology at McGill University.
ISG15 is a protein whose production rises strongly following interferon signaling during infection. Cells attach ISG15 to selected proteins through a process known as ISGylation, which can change protein activity and strengthen antiviral defenses.
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The SARS-CoV-2 fights back using PLpro, which removes ISG15 tags through deISGylation.
To determine how important this ability really is, the researchers engineered a SARS-CoV-2 mutant with PLpro mutations that severely impaired its ability to remove ISG15 while preserving other essential functions. The mutant virus was then tested against functioning antiviral defenses.
The mutant virus performed considerably worse when confronted by functioning antiviral defenses, showing reduced viral levels in several interferon-competent human cell types and producing lower viral titers and transcripts in infected mice.
Detailed experiments revealed that PLpro-mediated removal of ISG15 interfered with antiviral signaling involving MDA5-MAVS and TRIF, which operate as cellular alarm systems detecting signs of infection and helping initiate interferon-driven defenses.
PLpro appears to give SARS-CoV-2 an important advantage by interfering with the cell’s ability to sound an effective early antiviral alarm.
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One of the most significant discoveries was that deISGylation extended far beyond immune signaling, with metabolic studies showing that disabling PLpro’s ISG15-removing activity disrupted both glycolysis and the pentose phosphate pathway.
Mutant-virus-infected cells accumulated glucose-6-phosphate while showing reduced ribose-5-phosphate and ribulose-5-phosphate. The researchers also detected reduced glutathione, an important antioxidant that protects against oxidative damage.
Three metabolic enzymes emerged as important targets: ALDOA, G6PD, and other enzymes, which support glycolysis, the pentose phosphate pathway, and antioxidant defenses.
The study’s results identify viral deISGylation as a potentially important therapeutic target, although additional research is required to determine whether selectively blocking this activity can be safely translated into antiviral treatments.
The study findings were published in the peer-reviewed journal: Immunity.
