2. Academic Validation
  3. Viral SAM-binding proteins nsp14 and NP868R reprogram ATG4A-dependent autophagy from antiviral LC3B activity to GABARAP-mediated mitophagy

Viral SAM-binding proteins nsp14 and NP868R reprogram ATG4A-dependent autophagy from antiviral LC3B activity to GABARAP-mediated mitophagy

  • Autophagy. 2026 Jan 1:1-17. doi: 10.1080/15548627.2025.2608972.
Yahui Li 1 2,  Ya Zhu 1,  Fei Wang 1,  Xuezhi Ying 1,  Chenchen Zhao 1,  Wei Si 1,  Jiepeng Zhong 1,  Wei Yin 3,  Lulu Lin 1,  Jian Li 1,  Yan Yan 1,  Jiyong Zhou 1 4,  Boli Hu 1
Affiliations

Affiliations

  • 1 MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Zhejiang University, Hangzhou, China.
  • 2 College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, China.
  • 3 Core Facilities, School of Medicine, Zhejiang University, Hangzhou, China.
  • 4 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University, Hangzhou, China.
PMID: 41432349 DOI: 10.1080/15548627.2025.2608972
Abstract

Members of the mammalian Atg8-protein family (ATG8), including the MAP1LC3/LC3 and GABARAP subfamilies, play essential roles in selective macroautophagy/Autophagy. However, their functional distinctions during viral Infection remain poorly understood. Here, we show that S-adenosyl-L-methionine (SAM)-binding Viral Proteins, such as nsp14 from coronavirus and NP868R from African swine fever virus (ASFV), reprogram Autophagy by shifting Antiviral LC3B activity toward GABARAP-mediated Mitophagy in an ATG4A-dependent manner. Mechanistically, the SAM-binding motif allows these Viral Proteins to stabilize ATG4A mRNA, thereby increasing ATG4A expression and redirecting autophagic flux from LC3B-mediated virophagy to GABARAP-dependent Mitophagy. This shift suppresses innate immune responses by targeting both MAVS-dependent interferon signaling and virophagy, ultimately enhancing viral replication. Collectively, our findings uncover a previously unrecognized immune evasion strategy in which SAM-binding Viral Proteins rewire Autophagy from Antiviral to proviral pathways.Abbreviation: ACTB: actin beta; ATG: Autophagy related genes; ASFV: African swine fever virus; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CQ: chloroquine; CS: citrate synthase; ExoN: exoribonuclease; GABARAP: GABA type A receptor-associated protein; IFN: type I interferon; IFNB: interferon beta; IPEC-J2: intestinal porcine epithelial cell line-J2; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAVS: mitochondrial Antiviral signaling protein; MT-CO2/COX2: mitochondrially encoded cytochrome c oxidase II; nsp14: nonstructural protein 14; OPTN: optineurin; PEDV: porcine epidemic diarrhea virus; RNMT/N7-MTases: RNA guanine-7 methyltransferase; SAM: S-adenosyl-L-methionine; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 binding protein 1; TCID50: 50% tissue culture infective dose; TOMM70: translocase of outer mitochondrial membrane 70; TOMM20: translocase of outer mitochondrial membrane 20; WT: wild-type.

Keywords

ATG4A; ATG8 family; GABARAP; LC3B; mitophagy; virophagy.

Figures
Products
Inhibitors & Agonists
Other Products