biostudies-literatureClark AMNational Eye InstituteNEI NIH HHSResearch to Prevent BlindnessInternational Retinal Research FoundationNational Cancer InstituteNCI NIH HHSNIH HHSCancer Prevention and Research Institute of Texase162621https://www.ebi.ac.uk/biostudies/studies/S-EPMC10906455biostudies-literatureUnknown9(1)Syndromic ciliopathies and retinal degenerations are large heterogeneous groups of genetic diseases. Pathogenic variants in the CFAP418 gene may cause both disorders, and its protein sequence is evolutionarily conserved. However, the disease mechanism underlying CFAP418 mutations has not been explored. Here, we apply quantitative lipidomic, proteomic, and phosphoproteomic profiling and affinity purification coupled with mass spectrometry to address the molecular function of CFAP418 in the retina. We show that CFAP418 protein binds to the lipid metabolism precursor phosphatidic acid (PA) and mitochondrion-specific lipid cardiolipin but does not form a tight and static complex with proteins. Loss of Cfap418 in mice disturbs membrane lipid homeostasis and membrane-protein associations, which subsequently causes mitochondrial defects and membrane-remodeling abnormalities across multiple vesicular trafficking pathways in photoreceptors, especially the endosomal sorting complexes required for transport (ESCRT) pathway. Ablation of Cfap418 also increases the activity of PA-binding protein kinase Cα in the retina. Overall, our results indicate that membrane lipid imbalance is a pathological mechanism underlying syndromic ciliopathies and retinal degenerations which is associated with other known causative genes of these diseases.JCI insightDisruption of CFAP418 interaction with lipids causes widespread abnormal membrane-associated cellular processes in retinal degenerations.PMC10906455n/aP30CA125123R01 EY026521RP170005S10 OD016232EY014800S10 OD018210S10 OD021505P30 EY014800EY026521P30 CA125123Maschek JAZou JYang JClark AMNeiswanger GBurgoyne TYu DZhu DfalseDisruption of CFAP418 interaction with lipids causes widespread abnormal membrane-associated cellular processes in retinal degenerations.Syndromic ciliopathies and retinal degenerations are large heterogeneous groups of genetic diseases. Pathogenic variants in the CFAP418 gene may cause both disorders, and its protein sequence is evolutionarily conserved. However, the disease mechanism underlying CFAP418 mutations has not been explored. Here, we apply quantitative lipidomic, proteomic, and phosphoproteomic profiling and affinity purification coupled with mass spectrometry to address the molecular function of CFAP418 in the retina. We show that CFAP418 protein binds to the lipid metabolism precursor phosphatidic acid (PA) and mitochondrion-specific lipid cardiolipin but does not form a tight and static complex with proteins. Loss of Cfap418 in mice disturbs membrane lipid homeostasis and membrane-protein associations, which subsequently causes mitochondrial defects and membrane-remodeling abnormalities across multiple vesicular trafficking pathways in photoreceptors, especially the endosomal sorting complexes required for transport (ESCRT) pathway. Ablation of Cfap418 also increases the activity of PA-binding protein kinase Cα in the retina. Overall, our results indicate that membrane lipid imbalance is a pathological mechanism underlying syndromic ciliopathies and retinal degenerations which is associated with other known causative genes of these diseases.2024-01-01T00:00:00Z2024 Jan2025-04-04T20:40:49.684Z2025-04-04T20:40:49.684ZS-EPMC109064553797188010.1172/jci.insight.162621