ER–mitochondria associations are regulated by the VAPB–PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43
Radu Stoica,Kurt J. De Vos,Kurt J. De Vos,Sebastien Paillusson,Sarah M. Mueller,Rosa M. Sancho,Kwok-Fai Lau,Kwok-Fai Lau,Gema Vizcay-Barrena,Wen Lang Lin,Ya Fei Xu,Jada Lewis,Dennis W. Dickson,Leonard Petrucelli,Jacqueline C. Mitchell,Christopher Shaw,Christopher C.J. Miller +16 more
TLDR
It is demonstrated that the ER-resident protein VAPB interacts with the mitochondrial protein tyrosine phosphatase-interacting protein-51 (PTPIP51) to regulate ER–mitochondria associations and that TDP-43, a protein pathologically linked to amyotrophic lateral sclerosis and fronto-temporal dementia perturbs ER–Mitochondria interactions.Abstract:
Mitochondria and the endoplasmic reticulum (ER) form tight structural associations and these facilitate a number of cellular functions. However, the mechanisms by which regions of the ER become tethered to mitochondria are not properly known. Understanding these mechanisms is not just important for comprehending fundamental physiological processes but also for understanding pathogenic processes in some disease states. In particular, disruption to ER-mitochondria associations is linked to some neurodegenerative diseases. Here we show that the ER-resident protein VAPB interacts with the mitochondrial protein tyrosine phosphatase-interacting protein-51 (PTPIP51) to regulate ER-mitochondria associations. Moreover, we demonstrate that TDP-43, a protein pathologically linked to amyotrophic lateral sclerosis and fronto-temporal dementia perturbs ER-mitochondria interactions and that this is associated with disruption to the VAPB-PTPIP51 interaction and cellular Ca(2+) homeostasis. Finally, we show that overexpression of TDP-43 leads to activation of glycogen synthase kinase-3β (GSK-3β) and that GSK-3β regulates the VAPB-PTPIP51 interaction. Our results describe a new pathogenic mechanism for TDP-43.read more
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The BioPlex Network: A Systematic Exploration of the Human Interactome
Edward L. Huttlin,Lily Ting,Raphael J. Bruckner,Fana Gebreab,Melanie P. Gygi,John Szpyt,Stanley Tam,Gabriela Zarraga,Greg Colby,Kurt Baltier,Rui Dong,Virginia Guarani,Laura Pontano Vaites,Alban Ordureau,Ramin Rad,Brian K. Erickson,Martin Wühr,Joel M. Chick,Bo Zhai,Deepak Kolippakkam,Julian Mintseris,Robert A. Obar,Robert A. Obar,Tim Harris,Spyros Artavanis-Tsakonas,Spyros Artavanis-Tsakonas,Mathew E. Sowa,Pietro De Camilli,Joao A. Paulo,J. Wade Harper,Steven P. Gygi +30 more
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References
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Mitofusin 2 tethers endoplasmic reticulum to mitochondria
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Journal ArticleDOI
Autophagosomes form at ER–mitochondria contact sites
Maho Hamasaki,Nobumichi Furuta,Atsushi Matsuda,Atsushi Matsuda,Akiko Nezu,Akitsugu Yamamoto,Naonobu Fujita,Hiroko Oomori,Takeshi Noda,Tokuko Haraguchi,Tokuko Haraguchi,Yasushi Hiraoka,Yasushi Hiraoka,Atsuo Amano,Tamotsu Yoshimori +14 more
TL;DR: It is shown that autophagosomes form at the ER–mitochondria contact site in mammalian cells, and new insight is provided into organelle biogenesis by demonstrating that the ER-resident SNARE protein syntaxin 17 (STX17) binds ATG14 and recruits it to the ER—mitochondia contact site.