Clark, Anna;
Yu, Dongmei;
Neiswanger, Grace;
Zhu, Daniel;
Maschek, Alan;
Burgoyne, Thomas;
Yang, Jun;
(2022)
Disruption of CFAP418 interaction with lipids causes abnormal membrane-associated cellular processes in retinal degenerations.
bioRxiv: Cold Spring Harbor, NY, USA.
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Abstract
Syndromic ciliopathies and retinal degenerations are large heterogeneous groups of genetic diseases. CFAP418 is a causative gene of both disorders, and its protein sequence is evolutionarily conserved. However, the pathogenic mechanism caused by CFAP418 mutations is largely unknown. Here, we employed affinity purification coupled with mass spectrometry and quantitative lipidomic, proteomic, and phosphoproteomic approaches to address the molecular function of CFAP418 in mouse retinas. We showed that CFAP418 bound to lipid metabolism precursor phosphatidic acid (PA) and mitochondrion-specific lipid cardiolipin but did not form a tight and static complex with proteins. Loss of Cfap418 led to membrane lipid imbalance and protein-membrane association alteration, which subsequently caused mitochondrial defects and membrane remodeling abnormalities in multiple vesicular trafficking pathways. Loss of Cfap418 also increased the activity of PA-binding protein kinase Cα. Our results indicate that membrane lipid imbalance is a new pathological mechanism underlying syndromic ciliopathies and retinal degenerations, which is associated with other known causative genes for these diseases, such as RAB28 and BBS genes.
Type: | Working / discussion paper |
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Title: | Disruption of CFAP418 interaction with lipids causes abnormal membrane-associated cellular processes in retinal degenerations |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1101/2022.06.13.495990 |
Publisher version: | https://doi.org/10.1101/2022.06.13.495990 |
Language: | English |
Additional information: | This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions. |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10174343 |
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