Rabies virus matrix protein stabilizes RGS4 to curb ferroptosis and aid replication

Rabies virus, the prototypical lyssavirus, suppresses neuronal ferroptosis through lipid droplet biogenesis, an immune evasion strategy previously identified by the research team. A new study now reports the mechanistic link between lipid droplet formation and ferroptosis regulation during infection, centering on a regulatory axis the authors describe as RGS4-HERC2-NCOA4-FTH.

According to the study, rabies virus upregulates Regulator of G Protein Signaling 4 (RGS4), a ferroptosis-associated regulator, and this induction depends strictly on triglyceride synthesis and subsequent lipid droplet formation. Functionally, genetic or pharmacological inhibition of RGS4 elevates ferroptosis susceptibility, which in turn restricts viral replication.

The mechanistic chain works as follows. When RGS4 is depleted, levels of HERC2 fall, impairing the assembly of branched K48/K63 ubiquitin chains on NCOA4. These chains are essential for NCOA4’s proteasomal degradation, so their loss stabilizes NCOA4. Stabilized NCOA4 then promotes ferritinophagy, the autophagic degradation of ferritin, leading to loss of ferritin heavy chain (FTH) and ultimately inducing ferroptosis.

The lyssavirus matrix (M) protein directly counteracts this pathway. The researchers found that M protein inhibits RGS4 degradation via the Cys/N-degron system through incomplete autophagy, thereby stabilizing RGS4. Maintained RGS4 preserves HERC2 expression, promotes NCOA4 ubiquitination, and attenuates ferritinophagy. This reduces ferroptosis susceptibility and enables viral replication.

The findings, reported in PLOS Pathogens, unveil what the authors describe as a novel lyssavirus-specific regulatory axis that modulates ferroptosis, highlighting the role of ferroptosis in lyssavirus infection and pathogenesis. The work is based on cell biological and mechanistic experiments described in the study, and the reported pathway links viral protein function to iron metabolism and autophagy during infection.

Subject of Research: How the lyssavirus matrix protein stabilizes RGS4 to suppress ferroptosis during rabies virus infection

Article Title: Lyssavirus matrix protein stabilizes RGS4 to suppress ferroptosis via incomplete autophagy and iron metabolic reprogramming

Article References: Zhao, J., Chen, P., Sun, M., Liang, C., Fu, Z. F., Zhao, L., & Zhou, M. (2026). Lyssavirus matrix protein stabilizes RGS4 to suppress ferroptosis via incomplete autophagy and iron metabolic reprogramming. PLOS Pathogens, 22(10), e1014726. https://doi.org/10.1371/journal.ppat.1014726

Image Credits: AI Generated

DOI: 10.1371/journal.ppat.1014726

Keywords: rabies virus, lyssavirus, ferroptosis, RGS4, NCOA4, ferritinophagy, lipid droplets, matrix protein, autophagy, iron metabolism, viral replication, immune evasion