Oxidative protein folding in the endoplasmic reticulum: Tight links to the mitochondria-associated membrane (MAM)

Abstract

The production of secretory proteins at the ER (endoplasmic reticulum) depends on a ready supply of energy and metabolites as well as the close monitoring of the chemical conditions that favor oxidative protein folding. ER oxidoreductases and chaperones fold nascent proteins into their export-competent three-dimensional structure. Interference with these protein folding enzymes leads to the accumulation of unfolded proteins within the ER lumen, causing an acute organellar stress that triggers the UPR (unfolded protein response). The UPR increases the transcription of ER chaperones commensurate with the load of newly synthesized proteins and can protect the cell from ER stress. Persistant stress, however, can force the UPR to commit cells to undergo apoptotic cell death, which requires the emptying of ER calcium stores. Conversely, a continuous ebb and flow of calcium occurs between the ER and mitochondria during resting conditions on a domain of the ER that forms close contacts with mitochondria, the MAM (mitochondria-associated membrane). On the MAM, ER folding chaperones such as calnexin and calreticulin and oxidoreductases such as ERp44, ERp57 and Ero1α regulate calcium flux from the ER through reversible, calcium and redox-dependent interactions with IP3Rs (inositol 1,4,5-trisphophate receptors) and with SERCAs (sarcoplasmic/endoplasmic reticulum calcium ATPases). During apoptosis progression and depending on the identity of the ER chaperone and oxidoreductase, these interactions increase or decrease, suggesting that the extent of MAM targeting of ER chaperones and oxidoreductases could shift the readout of ER-mitochondria calcium exchange from housekeeping to apoptotic. However, little is known about the cytosolic factors that mediate the on/off interactions between ER chaperones and oxidoreductases with ER calcium channels and pumps. One candidate regulator is the multi-functional molecule PACS-2 (phosphofurin acidic cluster sorting protein-2). Recent studies suggest that PACS-2 mediates localization of a mobile pool of calnexin to the MAM in addition to regulating homeostatic ER calcium signaling as well as MAM integrity. Together, these findings suggest cytosolic, membrane and lumenal proteins combine to form a two-way switch that determines the rate of protein secretion by providing ions and metabolites and that appears to participate in the pro-apoptotic ER-mitochondria calcium transfer.

Protein Folding and Quality Control in the ER

“…In particular, a tight interaction between the ER and the mitochondria-associated membrane (MAM) is now emerging as a major cellular signaling hub (Fig. 3B) Simmen et al 2010). On the MAM, ER chaperones (CNX, BiP), oxidoreductases (ERp44, Ero1a), and Ca 2þ channels/pumps (IP3R3, SERCA2b, and Sig-1R) are enriched, thereby creating an ideal environment for oxidative protein folding, as well as the regulation of Ca 2þ flux (Gilady et al 2010).…”

ERManI (Endoplasmic Reticulum Class I α-Mannosidase) Is Required for HIV-1 Envelope Glycoprotein Degradation via Endoplasmic Reticulum-associated Protein Degradation Pathway

“…Intracellular reactive oxygen species is mainly produced by mitochondria as a byproduct from energy production. Indeed, ER contains a specialized subcompartment that is called the mitochondrial-associated ER membrane, which physically connects ER to mitochondria (33). In mammalian cells, mitochondrial-associated ER membrane is supported by a protein complex consisting of voltage-dependent anion channel and several other proteins (34).…”

Murine Diacylglycerol Acyltransferase-2 (DGAT2) Can Catalyze Triacylglycerol Synthesis and Promote Lipid Droplet Formation Independent of Its Localization to the Endoplasmic Reticulum

“…Several lipid biosynthetic enzymes are enriched in MAM, including phosphatidylserine synthase-1 and -2, phosphatidylethanolamine N-methyltransferase, and ACAT1 (22)(23)(24). MAM also has a role in mediating calcium exchange between the ER and mitochondria (25).…”