Membrane integrity changes upon viral infection activate sphingomyelinase SMPDL3B to restrict cGAS-STING signaling via cGAMP degradation, 2025, Wang+

[SNT Gatchaman]

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

Spoiler: Authors

Zhimeng Wang; Yanfei Hou; Peiyuan Liu; Ruinan Wu; Jiaming Yang; Shilong Fan; Zexu Peng; Xiaoxu Han; Bin Su; Conggang Zhang

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.

HIGHLIGHTS
• SMPDL3B expression is induced by viral infection and membrane-perturbing agents

• cGAMP-triggered dimerization of SMPDL3B is essential for its catalytic hydrolysis of cGAMP

• SMPDL3B facilitates viral infection by degrading cGAMP and restricting cGAS-STING signaling

• The GPI-anchored protein SMPDL3B senses membrane integrity and couples to immune regulation

Link | PDF | Immunity | Open Access

 

[SNT Gatchaman]

Selected quotes from discussion —

DNA viruses trigger innate immune responses through the cGAS-STING pathway, activated by the second messenger cGAMP. Although this pathway is essential for antiviral defense, the mechanisms that regulate cGAMP availability during infection remain incompletely understood.

We identified SMPDL3B as a virus-inducible cGAMP-degrading enzyme that modulates this pathway. […] we show that SMPDL3B is induced and stabilised by multiple viruses—and membrane perturbation more generally—across diverse cell types.

These findings not only uncover a mechanism by which viruses exploit host regulation of cGAMP but also suggest that targeting SMPDL3B could offer new strategies to enhance antiviral immunity or modulate inflammatory responses driven by aberrant cGAS-STING activation.

The broad responsiveness of SMPDL3B is reminiscent of the PRR NLRP3, which seems to act as a general sensor of membrane disturbance.

Although our findings suggest that SMPDL3B levels are regulated via endocytic pathways, the precise mechanisms linking viral infection, membrane integrity, and SMPDL3B induction remain to be defined.

As a GPI-anchored protein (GPI-AP), SMPDL3B is covalently linked to the plasma membrane and typically localized within membrane microdomains known as lipid rafts. A key feature of GPI-APs is their internalization from the cell surface via endocytosis and subsequent degradation in lyosomes. This trafficking process is highly sensitive to the organization and condition of lipid rafts. Under basal conditions, SMPDL3B protein levels are very low, likely due to continuous turnover through endocytic degradation.

Upon viral infection or treatment with membrane-modulating agents that perturb lipid raft dynamics, SMPDL3B levels markedly increase, consistent with known regulatory mechanisms of GPI-APs. As SMPDL3B stability is governed by membrane-trafficking processes, this may represent a novel post-translational control point for innate immune responses

We also show that both SMPDL3B and CD14—a GPI anchored protein involved in Toll-like receptor (TLR)4 signaling—are regulated by endocytic pathways.

In addition to its intracellular role, cGAMP can act as an ‘‘immunotransmitter,’’ spreading immune signals between cells. Recent studies have identified several transporters that facilitate intercellular transfer of cGAMP, and two studies have shown that viral particles themselves can deliver cGAMP into target cells to propagate immune activation.

These findings highlight the complexity of cGAMP regulation. Despite this progress, a long unanswered question was whether viral infections actively induce or regulate the activity of cGAMP-degrading enzymes. […] we have been able to show that virus-induced SMPDL3B functions as a cGAMP hydrolase, thereby dampening cGAS-STING signaling. Although our data demonstrate that viral infection triggers SMPDL3B expression and enhances viral replication, it remains possible that this induction serves as a host driven negative feedback mechanism to avoid excessive cGAS activation and prevent autoimmunity. From this perspective, SMPDL3B upregulation may represent an evolutionary compromise by the host rather than a strategy evolved by viruses.

In summary, our findings expand the functional repertoire of SMPDL3B, positioning it as a dual regulator of innate immunity, linking membrane perturbation with suppression of both TLR and cGAS-STING signaling.