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  • The EMBO Journal (2005) 24, 717 - 729
  • doi:10.1038/sj.emboj.7600559

Published online: 3 February 2005

PACS-2 controls endoplasmic reticulum–mitochondria communication and Bid-mediated apoptosis

Thomas Simmen, Joseph E Aslan, Anastassia D Blagoveshchenskaya, Laurel Thomas, Lei Wan, Yang Xianga, Sylvain F Feliciangeli, Chien-Hui Hung, Colin M Crumpb and Gary Thomas

  1. Vollum Institute, Portland, OR, USA

Correspondence to:

Gary Thomas, Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, USA. Tel.: +1 503 494 6955; Fax: +1 503 494 1218; E-mail: thomasg@ohsu.edu

aPresent address: Department of Molecular and Cellular Physiology and Medicine, Stanford University, Stanford, CA 94305, USA

bPresent address: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK

Received 12 August 2004; Accepted 15 December 2004

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:

    • apoptosis,
    • Bid,
    • endoplasmic reticulum,
    • mitochondria,
    • PACS-2