Conggang Zhang Group Reveals that Virus-Induced SMPDL3B Senses Membrane Integrity Changes to Suppress the cGAS–STING Pathway
Source：Conggang Zhang
2025-11-24
October 31, 2025, a research team led by Conggang Zhang at the School of Pharmaceutical Sciences, Tsinghua University, has uncovered a novel mechanism by which viral infection modulates innate immunity. Their study, published in Immunity and entitled “Membrane integrity changes upon viral infection activate sphingomyelinase SMPDL3B to restrict cGAS-STING signaling via cGAMP degradation”, identifies SMPDL3B as a previously unrecognized host-derived cGAMP hydrolase. The enzyme is induced and stabilized upon viral infection, thereby suppressing the cGAS–STING signaling pathway and promoting viral replication. Mechanistically, SMPDL3B, a GPI-anchored membrane protein, acts as a sensor of membrane integrity and functions as a negative regulator of innate immune activation.
The study demonstrates that infection with a broad range of viruses, including HSV-1, PRV, VACV, VSV, and SeV, robustly induces SMPDL3B expression and stabilization across multiple cell types and in mice. Similarly, membrane-disturbing agents such as PEI, Lipofectamine, and lipid nanoparticles (LNPs) also trigger SMPDL3B accumulation. Under physiological conditions, SMPDL3B expression remains low due to endocytosis-mediated degradation; however, viral infection or membrane perturbation prevents this degradation, resulting in protein stabilization. These findings establish SMPDL3B as a membrane integrity sensor that links cellular membrane stress to innate immune regulation.
Functionally, the authors show that SMPDL3B promotes viral infection, while its genetic ablation impairs viral replication both in vitro and in vivo. Mechanistic analyses reveal that SMPDL3B exhibits cGAMP hydrolytic activity, directly degrading the second messenger cGAMP to attenuate cGAS-STING signaling and facilitate viral immune evasion. Structural studies further demonstrate that cGAMP-induced dimerization of SMPDL3B is essential for its enzymatic activity, as mutations disrupting dimerization markedly reduce cGAMP hydrolysis. Consequently, SMPDL3B-deficient cells and mice accumulate higher levels of cGAMP, display enhanced STING activation, and show reduced viral propagation, exemplified by HSV-1 infection models.
Collectively, this study identifies SMPDL3B as a host cGAMP hydrolase that responds to membrane integrity disturbances, revealing a new mechanism through which viruses exploit host regulatory pathways to dampen innate immune responses. Beyond infection, these findings highlight a broader role for SMPDL3B in maintaining immune homeostasis under membrane stress.
This work also extends the Zhang group’s earlier discovery of SMPDL3A, a homologous enzyme induced by LXR-mediated lipid metabolic signaling, which likewise acts as a negative regulator of the cGAS-STING pathway. Notably, SMPDL3A and SMPDL3B respond to distinct physiological cues: lipid metabolism and membrane perturbation, respectively. Together, these axes illustrate how host cells fine-tune immune responses through metabolic and structural stress signals. By uncovering the SMPDL3B-cGAMP axis that connects membrane stress to innate immune modulation, this study provides a new conceptual framework for understanding the integration of infection, metabolism, and immune regulation, and opens potential avenues for therapeutic intervention in infectious, inflammatory, and autoimmune diseases.
This research was supported by the National Natural Science Foundation of China, the Tsinghua–Peking Center for Life Sciences, and the Beijing Natural Science Foundation.
Article Link：https://linkinghub.elsevier.com/retrieve/pii/S1074-7613(25)00461-3
The study demonstrates that infection with a broad range of viruses, including HSV-1, PRV, VACV, VSV, and SeV, robustly induces SMPDL3B expression and stabilization across multiple cell types and in mice. Similarly, membrane-disturbing agents such as PEI, Lipofectamine, and lipid nanoparticles (LNPs) also trigger SMPDL3B accumulation. Under physiological conditions, SMPDL3B expression remains low due to endocytosis-mediated degradation; however, viral infection or membrane perturbation prevents this degradation, resulting in protein stabilization. These findings establish SMPDL3B as a membrane integrity sensor that links cellular membrane stress to innate immune regulation.
Functionally, the authors show that SMPDL3B promotes viral infection, while its genetic ablation impairs viral replication both in vitro and in vivo. Mechanistic analyses reveal that SMPDL3B exhibits cGAMP hydrolytic activity, directly degrading the second messenger cGAMP to attenuate cGAS-STING signaling and facilitate viral immune evasion. Structural studies further demonstrate that cGAMP-induced dimerization of SMPDL3B is essential for its enzymatic activity, as mutations disrupting dimerization markedly reduce cGAMP hydrolysis. Consequently, SMPDL3B-deficient cells and mice accumulate higher levels of cGAMP, display enhanced STING activation, and show reduced viral propagation, exemplified by HSV-1 infection models.
Collectively, this study identifies SMPDL3B as a host cGAMP hydrolase that responds to membrane integrity disturbances, revealing a new mechanism through which viruses exploit host regulatory pathways to dampen innate immune responses. Beyond infection, these findings highlight a broader role for SMPDL3B in maintaining immune homeostasis under membrane stress.
This work also extends the Zhang group’s earlier discovery of SMPDL3A, a homologous enzyme induced by LXR-mediated lipid metabolic signaling, which likewise acts as a negative regulator of the cGAS-STING pathway. Notably, SMPDL3A and SMPDL3B respond to distinct physiological cues: lipid metabolism and membrane perturbation, respectively. Together, these axes illustrate how host cells fine-tune immune responses through metabolic and structural stress signals. By uncovering the SMPDL3B-cGAMP axis that connects membrane stress to innate immune modulation, this study provides a new conceptual framework for understanding the integration of infection, metabolism, and immune regulation, and opens potential avenues for therapeutic intervention in infectious, inflammatory, and autoimmune diseases.
This research was supported by the National Natural Science Foundation of China, the Tsinghua–Peking Center for Life Sciences, and the Beijing Natural Science Foundation.
Article Link：https://linkinghub.elsevier.com/retrieve/pii/S1074-7613(25)00461-3
