PACS-2 controls endoplasmic reticulum-mitochondria communication and Bid-mediated apoptosis.
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.
Simmen
Thomas
T
Vollum Institute, Portland, OR 97239-3098, USA.
Aslan
Joseph E
JE
Blagoveshchenskaya
Anastassia D
AD
Thomas
Laurel
L
Wan
Lei
L
Xiang
Yang
Y
Feliciangeli
Sylvain F
SF
Hung
Chien-Hui
CH
Crump
Colin M
CM
Thomas
Gary
G
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D006706:Homeostasis; D006801:Humans; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D021381:Protein Transport; D034741:RNA, Small Interfering; D033921:Vesicular Transport Proteins
D048868:Adaptor Proteins, Signal Transducing; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; C499638:PACS2 protein, human; D034741:RNA, Small Interfering; D033921:Vesicular Transport Proteins