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  3. Membrane integrity changes upon viral infection activate sphingomyelinase SMPDL3B to restrict cGAS-STING signaling via cGAMP degradation

Membrane integrity changes upon viral infection activate sphingomyelinase SMPDL3B to restrict cGAS-STING signaling via cGAMP degradation

  • Immunity. 2025 Nov 11;58(11):2670-2684.e10. doi: 10.1016/j.immuni.2025.10.007.
Zhimeng Wang 1,  Yanfei Hou 1,  Peiyuan Liu 2,  Ruinan Wu 1,  Jiaming Yang 1,  Shilong Fan 3,  Zexu Peng 4,  Xiaoxu Han 5,  Bin Su 5,  Conggang Zhang 6
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, China; SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan, Shanxi, China.
  • 2 School of Life Sciences, Tianjin University, Tianjin, China.
  • 3 Center for Structural Biology, Tsinghua University, Beijing, China.
  • 4 SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan, Shanxi, China.
  • 5 Beijing Key Laboratory for HIV/AIDS Research, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China.
  • 6 School of Pharmaceutical Sciences, State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, China; SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan, Shanxi, China. Electronic address: cgzhang@tsinghua.edu.cn.
PMID: 41175872 DOI: 10.1016/j.immuni.2025.10.007
Abstract

The cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-cyclic GMP-AMP (cGAMP)-stimulator of interferon genes (STING) pathway mediates Antiviral innate immunity upon sensing cytosolic DNA. Here, we examined the impact of sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B), a paralog of the LXR lipid metabolism-induced cGAMP-degrading enzyme SMPDL3A, on viral Infection. We found that SMPDL3B was induced and stabilized by both viral Infection and membrane-disturbing agents, suggesting a role in sensing membrane stress as an early signal of cellular danger. Deletion of SMPDL3B impaired DNA virus Infection. Upon induction, SMPDL3B suppressed cGAS-STING signaling and downstream transcriptional pathways, including the interferon response. Mechanistically, SMPDL3B functioned as a cGAMP hydrolase; cGAMP-induced SMPDL3B dimerization enabled its hydrolase activity and a negative feedback loop that dampened STING signaling. SMPDL3B-deficient cells had elevated cGAMP concentrations, and Smpdl3b-/- mice exhibited enhanced cGAMP accumulation, heightened immune activation, and reduced viral loads upon herpes simplex virus type 1 (HSV-1) Infection. Thus, SMPDL3B links membrane stress to modulation of cGAS-STING signaling through cGAMP degradation, with potential implications in the contexts of inflammation or autoimmunity.

Keywords

SMPDL3B; cGAMP; cGAS-STING signaling pathway; host-microbe interactions; innate immunity; viral infection.

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