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CFAP418 participates in membrane-associated cellular processes through binding lipids during ciliogenesis

ABSTRACT: iliopathies and retinal degenerative diseases are heterogeneous groups of genetic diseases. CFAP418 is a causative gene of both diseases, and its sequence is evolutionarily conserved. Here, we employ affinity purification coupled with mass spectrometry and quantitative lipidomic, proteomic, and phosphoproteomic approaches to address the function of CFAP418 in retinas. We show CFAP418 unexpectedly binds to 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 leads to a widespread disruption of membrane lipid homeostasis and changes in protein-membrane association, which subsequently causes mitochondrial morphological and functional defects and membrane remodeling abnormalities in multiple vesicular trafficking pathways. The signaling of PA-binding protein kinase Ca is increased. Our results indicate that membrane lipid imbalance is a new pathological mechanism underlying inherited ciliopathies and retinal degenerations, which is associated with other known causative RAB28 and BBS genes.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Jun Yang

PROVIDER: MSV000089424 | MassIVE | Thu May 05 13:14:00 BST 2022

REPOSITORIES: MassIVE

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Disruption of CFAP418 interaction with lipids causes widespread abnormal membrane-associated cellular processes in retinal degenerations.

Clark Anna M AM Yu Dongmei D Neiswanger Grace G Zhu Daniel D Zou Junhuang J Maschek J Alan JA Burgoyne Thomas T Yang Jun J

JCI insight 20240109 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 ...[more]

PMID: 37971880

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