The Lipid-Modifying Enzyme SMPDL3B Negatively Regulates Innate Immunity, 2015, Heinz et al.

[SNT Gatchaman]

The Lipid-Modifying Enzyme SMPDL3B Negatively Regulates Innate Immunity
Heinz; Baumann; Köberlin; Snijder; Gawish; Shui; Sharif; Aspalter; Müller; Kandasamy; Breitwieser; Pichlmair; Bruckner; Rebsamen; Blüml; Karonitsch; Fauster; Colinge; Bennett; Knapp; Superti-Furga

Lipid metabolism and receptor-mediated signaling are highly intertwined processes that cooperate to fulfill cellular functions and safeguard cellular homeostasis. Activation of Toll-like receptors (TLRs) leads to a complex cellular response, orchestrating a diverse range of inflammatory events that need to be tightly controlled.

Here, we identified the GPI-anchored Sphingomyelin Phosphodiesterase, Acid-Like 3B (SMPDL3B) in a mass spectrometry screening campaign for membrane proteins co-purifying with TLRs. Deficiency of Smpdl3b in macrophages enhanced responsiveness to TLR stimulation and profoundly changed the cellular lipid composition and membrane fluidity. Increased cellular responses could be reverted by re-introducing affected ceramides, functionally linking membrane lipid composition and innate immune signaling. Finally, Smpdl3b-deficient mice displayed an intensified inflammatory response in TLR-dependent peritonitis models, establishing its negative regulatory role in vivo.

Taken together, our results identify the membrane-modulating enzyme SMPDL3B as a negative regulator of TLR signaling that functions at the interface of membrane biology and innate immunity.

Link | PDF (Cell Reports)

 

[SNT Gatchaman]

Relates to findings presented in IIMEC15 - Alain Moreau.

Mouse study. Highlights —

• Identification of SMPDL3B as lipid-modulating phosphodiesterase on macrophages
• SMPDL3B as negative regulator of Toll-like receptor function. Smpdl3b-deficiency strongly affected macrophage lipid composition and fluidity and led to higher responsiveness to TLR stimulation
• Negative regulatory role for SMPDL3B in Toll-like receptor function
• Strong influence of SMPDL3B on membrane lipid composition and fluidity

 

[SNT Gatchaman]

Quotes from introduction —

Toll-like receptors (TLRs) are important sensors of pathogens as well as cellular and environmental stress [...] leads to a complex inflammatory response, orchestrating a diverse range of cellular functions such as cytokine secretion, cell migration, and antigen presentation.

Many proteins have been identified previously as regulators of TLRs [...] include accessory proteins involved in folding and vesicular transport, facilitators of receptor-ligand interactions, transcriptional regulators as well as intracellular proteins

Lipids are involved in most cellular processes by serving at the same time as structural components of membranes, energy storage molecules, and second messengers in signaling events

we report on the identification of SMPDL3B as a lipid modifying enzyme and demonstrate its involvement in the regulation of TLR-induced signaling processes. [...] this GPI-anchored glycoprotein is prominently expressed on macrophages and dendritic cells (DCs) and further strongly upregulated by TLR stimuli and interferon gamma (IFN-g).

Functionally, Smpdl3b-deficient macrophages and DCs showed hyper-responsiveness to TLR stimulation, suggesting a negative regulatory role for SMPDL3B in TLR-induced signaling.

Identifying a role in lipid metabolism, Smpdl3b knockdown or knockout macrophages showed a strong reduction in membrane order. This was further highlighted by changes associated with SMPDL3B depletion on the global cellular lipid composition [...] In particular, specific ceramide species appeared to be depleted

Supplementation of these lipids in Smpdl3b knockdown cells reverted their hyper-inflammatory phenotype,

Taken together, our results identify SMPDL3B as lipid-modifying enzyme that acts as a negative regulator of TLR signaling at the interface of lipid metabolism and inflammatory signaling.