Lyssavirus matrix protein stabilizes RGS4 to suppress ferroptosis via incomplete autophagy and iron metabolic reprogramming
4 affiliations
- 1National Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- 2Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- 3Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan, China
- 4Hubei Hongshan Laboratory, Wuhan, China
Abstract
Rabies virus (RABV), the prototypical lyssavirus, suppresses neuronal ferroptosis through lipid droplet (LD) biogenesis, which is a critical immune evasion strategy we previously identified. However, the mechanistic link between LD formation and ferroptosis regulation during RABV infection remains poorly defined. Here, we report that RABV upregulate Regulator of G Protein Signaling 4 (RGS4), a ferroptosis-associated regulator, and this induction is strictly dependent on triglyceride synthesis and subsequent LD formation. Functionally, genetic or pharmacological inhibition of RGS4 elevates ferroptosis susceptibility, thereby restricting viral replication. Mechanistically, RGS4 depletion reduces HERC2, impairing the assembly of branched K48/K63 ubiquitin chains on NCOA4, which is essential for its proteasomal degradation, thereby enhancing NCOA4 stability. Stabilized NCOA4 promotes ferritinophagy, leading to degradation of ferritin heavy chain (FTH) and ultimately inducing ferroptosis. Critically, we identified that the lyssavirus matrix (M) protein directly counteracts this pathway: M protein inhibits RGS4 degradation via the Cys/N-degron system through incomplete autophagy, stabilizing RGS4 to maintain HERC2 expression, promote NCOA4 ubiquitination, and attenuate ferritinophagy. This mechanism reduces ferroptosis susceptibility and enables viral replication. Our findings unveil a novel lyssavirus-specific regulatory axis, RGS4-HERC2-NCOA4-FTH, that modulates ferroptosis, highlighting the critical role of ferroptosis in lyssavirus infection and pathogenesis. Author summary: Rabies virus (RABV) evades the immune system by suppressing neuronal ferroptosis through lipid droplet (LD) biogenesis. Here, we uncover a novel regulatory axis through which RABV orchestrates this process: RABV infection upregulate the ferroptosis-associated regulator RGS4, which depends on triglyceride synthesis and LD formation. Mechanistically, RGS4 maintains the expression of the E3 ubiquitin ligase HERC2, which promotes branched K48/K63-linked ubiquitination and subsequent proteasomal degradation of NCOA4. This inhibits ferritinophagy and blocks ferritin heavy chain (FTH) degradation, thereby reducing ferroptosis susceptibility and enabling viral replication. Critically, RABV matrix (M) protein directly stabilizes RGS4 by interfering with its degradation via the Cys/N-degron system through incomplete autophagy. Furthermore, we identified this mechanism as a conserved pathway across lyssaviruses. In summary, our findings demonstrate that lyssavirus hijacks the RGS4-HERC2-NCOA4-FTH axis to reduce ferroptosis susceptibility, thereby revealing how lyssavirus M protein modulates ferroptosis to facilitate viral replication. This work elucidates a previously undefined mechanism of viral evasion and provides novel avenues for developing interventions against lyssavirus.
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BibTeX
@article{zhao2026lyssavirus,
title = {{Lyssavirus matrix protein stabilizes RGS4 to suppress ferroptosis via incomplete autophagy and iron metabolic reprogramming}},
author = {Jianqing Zhao and Pingping Chen and Meixin Sun and Chuan Liang and Zhen F. Fu and Ling Zhao and Ming Zhou},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014726},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014726},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Lyssavirus matrix protein stabilizes RGS4 to suppress ferroptosis via incomplete autophagy and iron metabolic reprogramming
AU - Jianqing Zhao
AU - Pingping Chen
AU - Meixin Sun
AU - Chuan Liang
AU - Zhen F. Fu
AU - Ling Zhao
AU - Ming Zhou
PY - 2026
DA - 2026/10/21
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014726
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014726
AB - Rabies virus (RABV), the prototypical lyssavirus, suppresses neuronal ferroptosis through lipid droplet (LD) biogenesis, which is a critical immune evasion strategy we previously identified. However, the mechanistic link between LD formation and ferroptosis regulation during RABV infection remains poorly defined. Here, we report that RABV upregulate Regulator of G Protein Signaling 4 (RGS4), a ferroptosis-associated regulator, and this induction is strictly dependent on triglyceride synthesis and subsequent LD formation. Functionally, genetic or pharmacological inhibition of RGS4 elevates ferroptosis susceptibility, thereby restricting viral replication. Mechanistically, RGS4 depletion reduces HERC2, impairing the assembly of branched K48/K63 ubiquitin chains on NCOA4, which is essential for its proteasomal degradation, thereby enhancing NCOA4 stability. Stabilized NCOA4 promotes ferritinophagy, leading to degradation of ferritin heavy chain (FTH) and ultimately inducing ferroptosis. Critically, we identified that the lyssavirus matrix (M) protein directly counteracts this pathway: M protein inhibits RGS4 degradation via the Cys/N-degron system through incomplete autophagy, stabilizing RGS4 to maintain HERC2 expression, promote NCOA4 ubiquitination, and attenuate ferritinophagy. This mechanism reduces ferroptosis susceptibility and enables viral replication. Our findings unveil a novel lyssavirus-specific regulatory axis, RGS4-HERC2-NCOA4-FTH, that modulates ferroptosis, highlighting the critical role of ferroptosis in lyssavirus infection and pathogenesis. Author summary: Rabies virus (RABV) evades the immune system by suppressing neuronal ferroptosis through lipid droplet (LD) biogenesis. Here, we uncover a novel regulatory axis through which RABV orchestrates this process: RABV infection upregulate the ferroptosis-associated regulator RGS4, which depends on triglyceride synthesis and LD formation. Mechanistically, RGS4 maintains the expression of the E3 ubiquitin ligase HERC2, which promotes branched K48/K63-linked ubiquitination and subsequent proteasomal degradation of NCOA4. This inhibits ferritinophagy and blocks ferritin heavy chain (FTH) degradation, thereby reducing ferroptosis susceptibility and enabling viral replication. Critically, RABV matrix (M) protein directly stabilizes RGS4 by interfering with its degradation via the Cys/N-degron system through incomplete autophagy. Furthermore, we identified this mechanism as a conserved pathway across lyssaviruses. In summary, our findings demonstrate that lyssavirus hijacks the RGS4-HERC2-NCOA4-FTH axis to reduce ferroptosis susceptibility, thereby revealing how lyssavirus M protein modulates ferroptosis to facilitate viral replication. This work elucidates a previously undefined mechanism of viral evasion and provides novel avenues for developing interventions against lyssavirus.
SN - 1553-7374
SN - 1553-7366
ER -