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This research investigates how UL48 proteins from alphaherpesviruses degrade STING1 to inhibit immune signaling.

February 19, 2026

Alphaherpesvirus UL48 homologs degrade STING1 by selective autophagy

Key Points

This research investigates how UL48 proteins from alphaherpesviruses degrade STING1 to inhibit immune signaling.
Examined the role of UL48 in STING1 degradation using pseudorabies virus (PRV) models.
Utilized E3 ligase TRIM21 to study the ubiquitination process of STING1.
Implemented autophagy inhibitors and analyzed lysosomal degradation pathways.
Compared effects in different alphaherpesvirus strains, including HSV-1 and CHV-2.
Demonstrated that UL48 triggers STING1 degradation via selective autophagy.
UL48 catalyzes STING1 ubiquitination creating K33/K63 linkages for degradation.
UL48-deficient mutants displayed reduced pathogenicity in a mouse model.
Identified that various UL48 homologs across herpesviruses also target STING1.

Abstract

Alpha-herpesviruses have evolved strategies to break through immune defenses and cause severe host damage. Here, we demonstrate that the tegument protein UL48 in pseudorabies virus (PRV) inhibits type I interferon signaling by triggering STING1 degradation via a selective macroautophagy/autophagy pathway. Mechanistically, UL48 recruits the E3 ligase TRIM21 (tripartite motif containing 21), which catalyzes the ubiquitination of STING1 to form a K33/K63 linkage and is captured by the cargo receptor CALCOCO2/NDP52 for lysosomal degradation. In addition, multiple α-herpesvirus tegument protein UL48 homologs also target STING1 for degradation. Importantly, this phenotype was also observed in other herpesviruses driven by PRV UL48 homologs (herpes simplex virus-1 HSV-1 and cercopithecine alphaherpesvirus 2 CHV-2). In addition, UL48-deficient PRV and HSV-1 mutant viruses attenuated pathogenicity in mice. In conclusion, this study describes a novel mechanism by which α-herpesviruses utilize UL48 proteins to promote viral escape from the host immune response.Abbreviations: 3-MA: 3-methyladenine; B-DNA: poly (dA:dT); BNIP3L/Nix: BCL2 interacting protein 3 like; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; cGAMP: cyclic GMP-AMPP; CGAS: cyclic GMP-AMP synthase; CHX: cyclohexane; CHV-2: cercopithecine herpesvirus 2; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DMSO: dimethyl sulfoxide; ER: endoplasmic reticulum; GFP: green fluorescent protein; H HSV-1: herpes simplex virus 1; IRF3: interferon regulatory factor 3; LIR: LC3-interacting region; MAP1LC3A/LC3: microtubule associated protein 1 light chain 3 alpha; MG132: cbz-leu-leu-leucinal; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; PRV: pseudorabies virus; sgRNA: single guide RNA; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; STING1/STING: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TOLLIP: toll interacting protein.

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Alphaherpesvirus UL48 homologs degrade STING1 by selective autophagy

Key Points

Abstract

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