TRIM22 blocks hepatitis B virus replication by tagging LDHA for destruction

Interferon-Powered Protein TRIM22 Strips Hepatitis B of Its Metabolic Fuel and Unmutes the Cell’s Viral Alarm

Scientists at Fujian Medical University in China have mapped a previously hidden circuit that ties cellular metabolism to innate antiviral immunity in hepatitis B — and the circuit turns on a molecular demolition tag. In a study published in the Journal of Translational Medicine, first author Jieying He and colleagues, working with corresponding authors Qishui Ou and Ni Lin, report that TRIM22, a protein produced in abundance when interferon reaches an infected cell, suppresses hepatitis B virus (HBV) replication by decorating lactate dehydrogenase A (LDHA), a central enzyme of glycolysis, with K48-linked ubiquitin chains: the canonical biochemical signal that dooms a protein to destruction by the proteasome. The consequences ripple in two directions at once. Clearing LDHA chokes off the glycolytic flux on which viral replication depends, and it simultaneously lifts a suppressive hand from the RIG-I-MAVS pathway, the sensor system that detects viral nucleic acids and rallies the interferon response. The result is a two-pronged, host-centered attack on a virus that has proven stubbornly resistant to single-target drugs.

Chronic hepatitis B remains one of medicine’s most intractable problems. Hundreds of millions of people worldwide carry the virus long-term, and in a substantial fraction of them the infection silently progresses toward cirrhosis and hepatocellular carcinoma, claiming hundreds of thousands of lives each year. Current antivirals — nucleoside and nucleotide analogues such as entecavir and tenofovir — potently suppress viral replication but almost never eradicate it, because HBV archives its genetic blueprint as covalently closed circular DNA in the nuclei of hepatocytes, a reservoir that these drugs cannot touch. Pegylated interferon-alpha, the other mainstay therapy, achieves durable control in only a minority of patients. Interferon-based regimens depend on coaxing the infected cell’s own antiviral genes into action, which is precisely why interferon-stimulated genes have become a hunting ground for new therapeutic targets. A “functional cure,” in which the immune system holds the virus in check without ongoing treatment, is widely regarded as the field’s ultimate goal, and that ambition has pushed researchers toward host-directed strategies that reprogram the infected cell itself.

The new study began with a clinical observation. The researchers collected serum samples from 208 patients with chronic hepatitis B and examined lactate dehydrogenase, or LDH, an enzyme that spills into the bloodstream when cells are damaged or metabolically revved up. Serum LDH levels correlated positively with both HBV viral load and standard markers of liver injury, including alanine aminotransferase and aspartate aminotransferase. LDH activity is a routine measurement in clinical chemistry, and its elevation in chronic hepatitis B has long been read as a nonspecific sign of hepatocyte damage; the new data suggest it also carries metabolic information that tracks viral activity far more directly. In other words, the more actively the virus replicated, the hotter the patients’ lactate metabolism appeared to run — a correlation consistent with the idea that HBV co-opts the glycolytic machinery of hepatocytes to fuel its own replication. Earlier work had already implicated LDHA, the subunit responsible for converting pyruvate into lactate, in promoting HBV replication. What remained missing was a regulatory mechanism: what, inside an infected liver, decides how much LDHA the virus gets to keep?

The Fujian team turned to TRIM22, a member of the tripartite motif family of proteins and a well-characterized interferon-stimulated gene. TRIM22 carries a RING domain, a catalytic module that allows it to function as an E3 ubiquitin ligase — the class of enzymes that, working with ubiquitin-activating E1 and ubiquitin-conjugating E2 enzymes, attaches ubiquitin tags to specific substrates and thereby decides their fate. Although TRIM22 has long been associated with antiviral defense, whether its ligase activity had anything to do with HBV, and whether that activity might intersect with cellular metabolism, was unknown. The first clue came from the public gene-expression dataset GSE65359, derived from liver tissue of patients with chronic hepatitis B: TRIM22 expression was negatively correlated with LDHA and with the lactate transporters SLC16A1 and SLC16A4, the membrane channels that export lactate from cells. The inverse relationship hinted that TRIM22 might act as a physiological brake on the very glycolytic program that HBV prefers.

To test that idea, the researchers established TRIM22-overexpressing cell models and interrogated them with transcriptomic sequencing, targeted metabolomics and Seahorse extracellular acidification rate (ECAR) analysis, a technique that measures real-time acid efflux as a live readout of glycolytic activity. The results were strikingly coherent. Overexpression of TRIM22 dampened glycolytic gene expression, shifted the metabolite landscape away from glycolytic intermediates, and measurably reduced ECAR, confirming that glycolytic flux itself — not merely the transcriptomic signature — had been suppressed. Targeted metabolomics reinforced the picture, revealing shifts in central carbon metabolites consistent with a slowdown of glycolysis. At the same time, the cells displayed signs of a reinvigorated tricarboxylic acid cycle, suggesting that pyruvate was being funneled back into mitochondrial respiration instead of being fermented to lactate. Transcriptomic comparisons pointed the same way, with glycolysis-linked genes sliding downward while immune signaling modules gained ground. Functionally, this metabolic rewiring carried an antiviral dividend: HBV replication markers fell in the TRIM22-enhanced cells.

The next question was mechanistic: how does TRIM22 reach into the glycolytic pathway at all? Using co-immunoprecipitation coupled to liquid chromatography–tandem mass spectrometry (LC-MS/MS), the team screened for proteins that physically associate with TRIM22 and identified LDHA as a novel interacting partner. Domain-mapping experiments with deletion mutants then pinpointed the anatomy of the interaction: TRIM22’s coiled-coil domain mediates the physical handshake with LDHA, while its RING domain catalyzes the attachment of K48-linked polyubiquitin chains to the enzyme. The linkage type matters enormously. K48 chains are the proteasome’s shipping label, directing the tagged protein to the proteasome for demolition, whereas K63 chains typically serve as signaling scaffolds. When the researchers blocked the proteasome with MG132, LDHA was rescued from TRIM22-driven degradation, sealing the case that TRIM22 functions as a bona fide E3 ligase for this glycolytic enzyme.

Destroying LDHA, it turned out, does far more than starve the virus; it unmutes innate immune signaling. In cells where TRIM22 degraded LDHA, the researchers documented enhanced activation of the retinoic acid-inducible gene I (RIG-I)–mitochondrial antiviral signaling protein (MAVS) pathway, the frontline sensor circuit for viral RNA. In this cascade, RIG-I recognizes foreign RNA and recruits MAVS on the outer mitochondrial membrane, which in turn activates TANK-binding kinase 1 (TBK1); phosphorylated TBK1 then phosphorylates interferon regulatory factor 3 (IRF3), which enters the nucleus and switches on interferon-beta and a battery of interferon-stimulated genes. The revival of this pathway matters because HBV, although formally a DNA virus, transcribes its genome through RNA intermediates, giving RNA sensors a legitimate molecular target at multiple points in its life cycle. That sequence ran measurably hotter when LDHA was removed, and HBV markers — hepatitis B surface antigen, e antigen, core antigen and viral DNA — declined in parallel. The study thereby connects a metabolic enzyme to an immune checkpoint: as long as LDHA remains abundant, the alarm stays muffled; when TRIM22 clears LDHA, the alarm switches on.

The team then ran the logic in reverse. When LDHA was overexpressed, HBV replication climbed and the RIG-I-MAVS pathway was measurably suppressed. Transcriptomic analysis traced part of this immunosuppressive effect to the downregulation of two chemokine genes, CCL3L1 and CCL24, which the authors propose may act as intermediaries between glycolytic activity and antiviral signaling; chemokines of this kind help orchestrate the recruitment and positioning of antiviral immune cells, so their loss offers a plausible route by which a metabolic enzyme could quietly damp the body’s defenses. Functional rescue experiments cemented the causal chain: co-transfecting cells with LDHA partially restored viral replication even in the presence of TRIM22, and treatment with amlexanox, an approved anti-inflammatory drug frequently used to probe the TBK1–IRF3 axis, was deployed to test the pathway’s contribution. Together, the gain-of-function and loss-of-function data establish that LDHA is not a passive bystander in HBV infection but an active suppressor of innate immunity whose presence the virus exploits.

The therapeutic implications are layered. The work supplies a mechanistic rationale for LDHA inhibitors as host-directed anti-HBV agents — a class of compounds already under development in oncology, where tumor cells’ addiction to aerobic glycolysis has made LDHA a drug target in its own right. It also highlights the appeal of engineered degradation strategies: proteolysis-targeting chimeras, or PROTACs, co-opt the cell’s own ubiquitin-proteasome system to destroy disease-relevant proteins, and the TRIM22–LDHA axis shows that removing LDHA would pay a double dividend, cutting the virus’s fuel supply while disinhibiting innate immunity. The findings may also illuminate why interferon therapy works at all: interferon potently induces TRIM22, so part of its antiviral effect could plausibly flow through this newly described ubiquitination circuit. And because the mechanism is enzymatic and structurally defined — a RING domain acting on a named substrate — it hands medicinal chemists a concrete blueprint rather than a loose correlation.

The authors are appropriately cautious about the distance between culture dish and clinic. The mechanistic work rests on overexpression models, domain-deletion mutants and pharmacologic probes, supported by clinical correlation in patient sera, and the paper was released early as a citable, peer-reviewed accepted manuscript whose final version of record is still pending minor editorial edits. Clinical translation will require showing that pharmacologically lowering LDHA — or boosting TRIM22 — in genuinely infected livers suppresses HBV without unacceptable toxicity, a nontrivial demand given that LDHA is central to energy metabolism in muscle and red blood cells. Even so, the study defines a clean, testable mechanism: an interferon-stimulated E3 ligase ubiquitinates a glycolytic enzyme through its RING domain, weakening the virus’s metabolic supply line while amplifying the RIG-I-MAVS alarm. For a virus that has outmaneuvered direct-acting drugs for decades, an attack on its fuel — and on its silencing grip over the immune system — opens an inviting new flank. The work was supported in part by the National Natural Science Foundation of China and Fujian provincial research programs.