PACS-2 Controls Endoplasmic Reticulum-mitochondria Communication and Bid-mediated Apoptosis

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2005 Feb 5

PMID 15692567

Citations 267

Authors

Thomas Simmen

Joseph E Aslan

Anastassia D Blagoveshchenskaya

Laurel Thomas

Lei Wan

Yang Xiang

Sylvain F Feliciangeli

Chien-Hui Hung

Colin M Crump

Gary Thomas

Affiliations

Soon will be listed here.

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.

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