Proteins of the PDI family: Unpredicted non‐ER locations and functions

Abstract

Protein disulfide isomerases (PDIs) constitute a family of structurally related enzymes which catalyze disulfide bonds formation, reduction, or isomerization of newly synthesized proteins in the lumen of the endoplasmic reticulum (ER). They act also as chaperones, and are, therefore, part of a quality-control system for the correct folding of the proteins in the same subcellular compartment. While their functions in the ER have been thoroughly studied, much less is known about their roles in non-ER locations, where, however, they have been shown to be involved in important biological processes. At least three proteins of this family from higher vertebrates have been found in unusual locations (i.e., the cell surface, the extracellular space, the cytosol, and the nucleus), reached through an export mechanism which has not yet been understood. In some cases their function in the non-ER location is clearly related to their redox properties, but in most cases their mechanism of action has still to be disclosed, although their propensity to associate with other proteins or even with DNA might be the main factor responsible for their activities.

Protein Disulfide Isomerase-2 of Arabidopsis Mediates Protein Folding and Localizes to Both the Secretory Pathway and Nucleus, Where It Interacts with Maternal Effect Embryo Arrest Factor

“…An auxin-binding protein with a KDEL sequence exits the ER and travels to the plasma membrane (Jones and Herman, 1993). Likewise, in rat exocrine pancreatic cells, a PDI containing a KDEL signal traffics from the ER through the secretory pathway to the plasma membrane (Turano et al, 2002;Yoshimori et al, 1990). The KDEL motif at the C-terminus of PDI2 may ensure temporary ER residency, but could be overridden by other signals to allow export from the ER to the Golgi, vacuole or apoplasm.…”

“…Thus, this work raises the significant question about how PDI2 can enter both the secretory and non-secretory pathways. Mammalian PDI is cellularly distributed beyond the ER, with reports of its detection in the cytosol, cell surface and the nucleus (reviewed in Turano et al, 2002). Examples of proteins that exhibit dual localization to the ER and nucleus include the PDI homolog ERp57/GRP58 (Adikesavan et al, 2008), yeast ubiquitin ligase (Swanson et al, 2001), and parathyroid related protein (Amaya et al, 2008).…”

“…PDIs are required for cell viability (Ferrari and Soling, 1999) and differentiation (Ohtani et al, 1993), ion uptake (Honscha et al, 1993), regulating transcription (Markus and Benezra, 1999) and are found in the nucleus, cytoplasm, ER, mitochondria, and extracellular milieu (Couet et al, 1996;Lahav et al, 2000;Rigobello et al, 2001;Turano et al, 2002;Wilson et al, 1998). Recently, human PDI was found to bind signal peptide peptidase and unfold target proteins, leading to their dislocation from the ER to the cytoplasm and degradation by the ubiquitin-proteasome system, which is a process known as ER-associated degradation (ERAD) (Lee et al, 2010).…”

Inhibition of thiol isomerase activity diminishes endothelial activation of plasminogen, but not of protein C

“…PDI also resides outside the endoplasmic reticulum, at a variety of sites which include the exofacial surface of the plasma membrane [4], where it is available for regulation of allosteric disulphide bonds in proteins of the haemostasis system. Activated platelets release PDI and a pool of PDI is found at the platelet cell surface [5].…”

MHC Class I Quality Control

“…The protein structure is made up of four domains a, b, a' and b' (Ferrari and Soling 1999;Silvennoinen, Myllyharju et al 2004). ERp57 is mainly, but not exclusively, an ER resident protein (Turano, Coppari et al 2002) with a C-terminal Gln-Glu-Asp-Leu (QEDL) retention signal (Urade, Oda et al 1997) and two thioredoxin domains with CGHC motifs shared with ERp72, protein disulfide isomerase (PDI) and other members of the thioredoxin family. Not only have many names been designated to this protein but several different functions of ERp57 have also been suggested including thiol-dependent oxidoreductase (Bourdi, Demady et al 1995;Hirano, Shibasaki et al 1995), cysteine protease (Urade and Kito 1992;Urade, Nasu et al 1992), carnitine palmitoyl transferase (Wada, Imai et al 1995), a hormone induced protein of the brain ) and in combination with calnexin and/or calreticulin as a chaperone for Nglycosylated proteins in the ER (Oliver, van der Wal et al 1997).…”