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Published on: January 22, 2019
Triglycerides induce endoplasmic reticulum lipid bilayer stress to activate PERK and enhance antifungal immunity
Han Wu1, Qing Shui1, Xiaoxi Luan1
1State Key Laboratory of Reproductive Medicine and Offspring Health, Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection Immunity and Disease Intervention of Shandong Province, Shandong University, Jinan 250012, Shandong, P.R. China; Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan 250012, Shandong, P.R. China.
Abstract:
Invasive fungal infections remain a major clinical challenge due to limited antifungal drugs, drug toxicity, and resistance. Fungal infections trigger endoplasmic reticulum (ER) stress. However, the mechanism through which this stress response affects antifungal immunity remains unclear. Here, we showed that de novo triglyceride synthesis promotes antifungal innate immune signaling and proinflammatory gene expression in macrophages. Upon fungal stimulation, triglycerides induce ER lipid bilayer stress and activate the protein kinase R (PKR)-like ER kinase (PERK) branch of the unfolded protein response pathway. Furthermore, activated PERK mediates autophagic degradation of Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) to amplify spleen tyrosine kinase-associated antifungal signaling. Mice with PERK deficiency in myeloid cells are more susceptible to the lethal sequelae of systemic infection with Candida albicans. Notably, administration of the PERK agonist CCT020312 improved host outcomes in disseminated fungal infections. Overall, our study identified a critical function of PERK in positively regulating antifungal immune responses and offers a potential therapeutic strategy for controlling C. albicans infections.
Insights
De novo triglyceride synthesis enhances antifungal immunity by activating the PERK pathway in macrophages. This pathway is crucial for controlling Candida albicans infections and offers a potential therapeutic target.
Area of Science:
- Immunology
- Cellular Biology
- Infectious Diseases
Background:
- Invasive fungal infections pose significant clinical challenges due to drug resistance and toxicity.
- Fungal infections induce endoplasmic reticulum (ER) stress, but its role in antifungal immunity is not fully understood.
Purpose of the Study:
- To investigate the role of de novo triglyceride synthesis in antifungal innate immune responses.
- To elucidate the mechanism by which ER stress impacts antifungal immunity.
Main Methods:
- Stimulation of macrophages with fungal pathogens.
- Analysis of triglyceride synthesis, ER stress markers, and immune signaling pathways.
- Assessment of host susceptibility in mice with myeloid-specific PERK deficiency.
- Evaluation of a PERK agonist in disseminated fungal infection models.
Main Results:
- De novo triglyceride synthesis promotes antifungal innate immune signaling and inflammation in macrophages.
- Triglycerides activate the PERK pathway of the unfolded protein response, leading to SHP-1 degradation and enhanced antifungal signaling.
- Mice lacking PERK in myeloid cells exhibit increased susceptibility to Candida albicans infection.
- Administration of a PERK agonist improved outcomes in disseminated fungal infections.
Conclusions:
- PERK signaling is critical for mounting effective antifungal immune responses.
- Targeting the PERK pathway represents a potential therapeutic strategy against invasive fungal infections, particularly Candida albicans.
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