title: The ER-Mitochondria Tethering Complex VAPB-PTPIP51 Regulates Autophagy.
abstract: Mitochondria form close physical associations with the endoplasmic reticulum (ER) that regulate a number of physiological functions. One mechanism by which regions of ER are recruited to mitochondria involves binding of the ER protein VAPB to the mitochondrial protein PTPIP51, which act as scaffolds to tether the two organelles. Here, we show that the VAPB-PTPIP51 tethers regulate autophagy. We demonstrate that overexpression of VAPB or PTPIP51 to tighten ER-mitochondria contacts impairs, whereas small interfering RNA (siRNA)-mediated loss of VAPB or PTPIP51 to loosen contacts stimulates, autophagosome formation. Moreover, we show that expression of a synthetic linker protein that artificially tethers ER and mitochondria also reduces autophagosome formation, and that this artificial tether rescues the effects of siRNA loss of VAPB or PTPIP51 on autophagy. Thus, these effects of VAPB and PTPIP51 manipulation on autophagy are a consequence of their ER-mitochondria tethering function. Interestingly, we discovered that tightening of ER-mitochondria contacts by overexpression of VAPB or PTPIP51 impairs rapamycin- and torin 1-induced, but not starvation-induced, autophagy. This suggests that the regulation of autophagy by ER-mitochondria signaling is at least partly dependent upon the nature of the autophagic stimulus. Finally, we demonstrate that the mechanism by which the VAPB-PTPIP51 tethers regulate autophagy involves their role in mediating delivery of Ca2+to mitochondria from ER stores. Thus, our findings reveal a new molecular mechanism for regulating autophagy.
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 9RX, UK.
authors.forename: Patricia
authors.initials: P
authors.lastname: Gomez-Suaga
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 9RX, UK.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Paillusson
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 9RX, UK.
authors.forename: Radu
authors.initials: R
authors.lastname: Stoica
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 9RX, UK.
authors.forename: Wendy
authors.initials: W
authors.lastname: Noble
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 9RX, UK.
authors.forename: Diane P
authors.initials: DP
authors.lastname: Hanger
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 9RX, UK. Electronic address: chris.miller@kcl.ac.uk.
authors.forename: Christopher C J
authors.initials: CCJ
authors.lastname: Miller
mesh_terms: D001343:Autophagy; D001798:Blood Proteins / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology; D013217:Starvation; D033921:Vesicular Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D001798:Blood Proteins; D007166:Immunosuppressive Agents; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; C496748:VAPB protein, human; D033921:Vesicular Transport Proteins; C031024:torin; D017027:Protein Tyrosine Phosphatases; C515449:RMDN3 protein, human; D002118:Calcium; D020123:Sirolimus
keywords: Alzheimer’s disease; MAM; PTPIP51; Parkinson’s disease; VAPB; amyotrophic lateral sclerosis; autophagy; calcium; endoplasmic reticulum; mitochondria