10.6084/m9.figshare.7701266.v2
Dongxue Mao
Dongxue
Mao
Guang Lin
Guang
Lin
Burak Tepe
Burak
Tepe
Zhongyuan Zuo
Zhongyuan
Zuo
Kai Li Tan
Kai
Li Tan
Mumine Senturk
Mumine
Senturk
Sheng Zhang
Sheng
Zhang
Benjamin R Arenkiel
Benjamin R
Arenkiel
Marco Sardiello
Marco
Sardiello
Hugo J. Bellen
Hugo
J. Bellen
VAMP associated proteins are required for autophagic and lysosomal degradation by promoting a PtdIns4P-mediated endosomal pathway
Taylor & Francis Group
2019
ALS8
autophagy
PI4KB
Vap33
VAPA/VAPB
2019-02-21 05:05:11
Dataset
https://tandf.figshare.com/articles/dataset/VAMP_associated_proteins_are_required_for_autophagic_and_lysosomal_degradation_by_promoting_a_PtdIns4P-mediated_endosomal_pathway/7701266
<p>Mutations in the ER-associated VAPB/ALS8 protein cause amyotrophic lateral sclerosis and spinal muscular atrophy. Previous studies have argued that ER stress may underlie the demise of neurons. We find that loss of VAP proteins (VAPs) leads to an accumulation of aberrant lysosomes and impairs lysosomal degradation. VAPs mediate ER to Golgi tethering and their loss may affect phosphatidylinositol-4-phosphate (PtdIns4P) transfer between these organelles. We found that loss of VAPs elevates PtdIns4P levels in the Golgi, leading to an expansion of the endosomal pool derived from the Golgi. Fusion of these endosomes with lysosomes leads to an increase in lysosomes with aberrant acidity, contents, and shape. Importantly, reducing PtdIns4P levels with a PtdIns4-kinase (PtdIns4K) inhibitor, or removing a single copy of Rab7, suppress macroautophagic/autophagic degradation defects as well as behavioral defects observed in <i>Drosophila Vap33</i> mutant larvae. We propose that a failure to tether the ER to the Golgi when VAPs are lost leads to an increase in Golgi PtdIns4P levels, and an expansion of endosomes resulting in an accumulation of dysfunctional lysosomes and a failure in proper autophagic lysosomal degradation.</p> <p><b>Abbreviations:</b> ALS: amyotrophic lateral sclerosis; CSF: cerebrospinal fluid; CERT: ceramide transfer protein; FFAT: two phenylalanines in an acidic tract; MSP: major sperm proteins; OSBP: oxysterol binding protein; PH: pleckstrin homology; PtdIns4P: phosphatidylinositol-4-phosphate; PtdIns4K: phosphatidylinositol 4-kinase; UPR: unfolded protein response; VAMP: vesicle-associated membrane protein; VAPA/B: mammalian VAPA and VAPB proteins; VAPs: VAMP-associated proteins (referring to <i>Drosophila</i> Vap33, and human VAPA and VAPB)</p>