PMID:15692567

Citation	Simmen, T, Aslan, JE, Blagoveshchenskaya, AD, Thomas, L, Wan, L, Xiang, Y, Feliciangeli, SF, Hung, CH, Crump, CM and Thomas, G (2005) PACS-2 controls endoplasmic reticulum-mitochondria communication and Bid-mediated apoptosis. EMBO J. 24:717-29
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.
Links	PubMed PMC549619 Online version:10.1038/sj.emboj.7600559
Keywords	Adaptor Proteins, Signal Transducing/deficiency; Adaptor Proteins, Signal Transducing/genetics; Adaptor Proteins, Signal Transducing/metabolism; Apoptosis; BH3 Interacting Domain Death Agonist Protein; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cell Line, Tumor; Endoplasmic Reticulum/metabolism; Endoplasmic Reticulum/ultrastructure; Homeostasis; Humans; Microscopy, Electron; Mitochondria/metabolism; Mitochondria/ultrastructure; Protein Transport; RNA, Small Interfering; Vesicular Transport Proteins
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:PACS2		GO:1990456: mitochondrion-ER tethering	ECO:0000315:		P		Human PACS2//The depletion of PACS‐2, but not PACS‐1, caused extensive mitochondrial fragmentation, and appeared to uncouple the fragmented mitochondria from the ER (Figure 1E)	complete CACAO 12300
HUMAN:PACS2		GO:0032469: endoplasmic reticulum calcium ion homeostasis	ECO:0000315:		P		Human PACS-2 Fig. 3C, histamine elicited a two-fold greater increase in calcium released from the ER into the cytosol of PACS-2-depleted cells compared to PACS-1-depleted or control cells.	complete CACAO 12400
HUMAN:PACS2		GO:0006915: apoptotic process	ECO:0000315:		P		Human PACS-2 depletion conferred a marked resistance to STS, increasing the percentage of viable cells by nearly four-fold. The antiapoptotic effects of the PACS-2 siRNA were corroborated by analyzing the STS-mediated caspase cleavage of poly-ADP-ribose polymerase (PARP) to generate p85.	complete CACAO 12401

References

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