TY - JOUR
T1 - PACS-2 controls endoplasmic reticulum-mitochondria communication and Bid-mediated apoptosis
AU - Simmen, Thomas
AU - Aslan, Joseph E.
AU - Blagoveshchenskaya, Anastassia D.
AU - Thomas, Laurel
AU - Wan, Lei
AU - Xiang, Yang
AU - Feliciangeli, Sylvain F.
AU - Hung, Chien Hui
AU - Crump, Colin M.
AU - Thomas, Gary
PY - 2005/2/23
Y1 - 2005/2/23
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Bid
KW - Endoplasmic reticulum
KW - Mitochondria
KW - PACS-2
UR - http://www.scopus.com/inward/record.url?scp=20144385980&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=20144385980&partnerID=8YFLogxK
U2 - 10.1038/sj.emboj.7600559
DO - 10.1038/sj.emboj.7600559
M3 - Article
C2 - 15692567
AN - SCOPUS:20144385980
SN - 0261-4189
VL - 24
SP - 717
EP - 729
JO - EMBO Journal
JF - EMBO Journal
IS - 4
ER -