PACS-2 controls endoplasmic reticulum–mitochondria communication and Bid-mediated apoptosis
Open Access
- 3 February 2005
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 24 (4), 717-729
- https://doi.org/10.1038/sj.emboj.7600559
Abstract
The endoplasmic reticulum (ER) and mitochondria form contacts that support communication between these two organelles, including synthesis and transfer of lipids, and the exchange of calcium, which regulates ER chaperones, mitochondrial ATP production, and apoptosis. Despite the fundamental roles for ER–mitochondria contacts, little is known about the molecules that regulate them. Here we report the identification of a multifunctional sorting protein, PACS‐2, that integrates ER–mitochondria communication, ER homeostasis, and apoptosis. PACS‐2 controls the apposition of mitochondria with the ER, as depletion of PACS‐2 causes BAP31‐dependent mitochondria fragmentation and uncoupling from the ER. PACS‐2 also controls formation of ER lipid‐synthesizing centers found on mitochondria‐associated membranes and ER homeostasis. However, in response to apoptotic inducers, PACS‐2 translocates Bid to mitochondria, which initiates a sequence of events including the formation of mitochondrial truncated Bid, the release of cytochrome c , and the activation of caspase‐3, thereby causing cell death. Together, our results identify PACS‐2 as a novel sorting protein that links the ER–mitochondria axis to ER homeostasis and the control of cell fate, and provide new insights into Bid action.Keywords
This publication has 43 references indexed in Scilit:
- Proapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and DeathScience, 2001
- Deletion of Yeast p24 Genes Activates the Unfolded Protein ResponseMolecular Biology of the Cell, 2001
- Organellar relationships in the Golgi region of the pancreatic beta cell line, HIT-T15, visualized by high resolution electron tomographyProceedings of the National Academy of Sciences of the United States of America, 2001
- Posttranslational N-Myristoylation of BID as a Molecular Switch for Targeting Mitochondria and ApoptosisScience, 2000
- The machinery of local Ca2+ signalling between sarco‐endoplasmic reticulum and mitochondriaThe Journal of Physiology, 2000
- Phosphatidylserine Synthase-1 and -2 Are Localized to Mitochondria-associated MembranesPublished by Elsevier BV ,2000
- Caspase-Resistant BAP31 Inhibits Fas-Mediated Apoptotic Membrane Fragmentation and Release of Cytochrome cfrom MitochondriaMolecular and Cellular Biology, 2000
- Mutants Affecting the Structure of the Cortical Endoplasmic Reticulum in Saccharomyces cerevisiaeThe Journal of cell biology, 2000
- The Dynamin-like Protein DLP1 Is Essential for Normal Distribution and Morphology of the Endoplasmic Reticulum and Mitochondria in Mammalian CellsMolecular Biology of the Cell, 1999
- Yama/CPP32β, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymeraseCell, 1995