From antibodies to adiponectin: role of ERp44 in sizing and timing protein secretion

Abstract

A large fraction of the proteome is synthesized and folded in the endoplasmic reticulum (ER), a multifunctional compartment also playing pivotal roles in Ca 2+ storage, redox homeostasis and signalling. From the ER, secretory proteins begin their journey towards their final destinations, the organelles of the exocytic and endocytic compartments, the plasma membrane or the extracellular space. Fidelity of protein-based intracellular communication is guaranteed by quality control (QC) mechanisms located at the ER-Golgi interface, which restrict forward transport to native proteins. QC is used also to time or shape the secretome. Furthermore, professional secretory cells face a problem of quantity, as well as quality of their protein products. This essay summarizes recent findings that identify ERp44 as a key regulator of protein secretion, Ca 2+ signalling and redox regulation. Keywords: early secretory pathway, endoplasmic reticulum, ERAD, protein quality control, secretion Date submitted 26 March 2010; date of final acceptance 31 May 2010 IntroductionIn multicellular organisms, cells must respond promptly to environmental stimuli, undergoing differentiation, motility, apoptosis or other responses. To take the right decision, cells need to continuously exchange information amongst each other and with the external world, and to unambiguously integrate the corresponding signals. Communication can occur among cells in close proximity to one another (contactdependent signalling), as well as through short-and long-range secretion. Virtually all receptors and most ligands employed in cell cross-talks are protein based, and the fidelity of the process requires that interacting proteins adopt their correct three-dimensional shape. This pressure explains why stringent proofreading systems evolved in eukaryotes, which survey on inter-and intracellular dialogues. Under this point of view, therefore, the stepwise tuning of protein folding, assembly and transport along the secretory route (both ligands and receptors are generally secretory molecules) goes under the definition of architectural editing or quality control (QC [1,2]). In general terms, this means that only native conformers can proceed along the secretory pathway, whereas aberrant, unfolded or unassembled proteins are retained inside the cell and-if not fixed in due time-eventually degraded to maintain homeostasis [3,4]. The logics of this important cellular device can be summarized in the need to couple the fidelity of released products with the efficiency of secretion. Some specialized cells, such as pancreatic cells, thyrocytes and B-lymphocytes, for instance, face the task of producing Correspondence to: R. Sitia, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Università Vita-Salute San Raffaele, Via Olgettina 58, Milan, Italy. E-mail: r.sitia@hsr.it humongous quantities of certain proteins: in general, such cells display a highly developed ER and exocytic pathway to comply with their function. Studying their characteristics teaches...

Glutathione- and non-glutathione-based oxidant control in the endoplasmic reticulum

“…In the absence of substrate oxidation it can, however, also produce H 2 O 2 or O 2 -, which is referred to as electron uncoupling. (Cortini and Sitia, 2010). Although speculative at present, it is formally possible that a similar mechanism accounts for Ero1-dependent accumulation of mitochondrial ROS upon induction of ER stress in C. elegans (Harding et al, 2003), in which both IP 3 R and ERp44 are conserved.…”

YajL, Prokaryotic Homolog of Parkinsonism-associated Protein DJ-1, Functions as a Covalent Chaperone for Thiol Proteome

“…Erp44 retains incompletely folded immunoglobulins and adiponectin in the endoplasmic reticulum (28); PDILT (protein disulfide isomerase-like of the testis) engages in disulfide-dependent interactions with a few uncharacterized substrates in testis (34); and AGR2 (anterior gradient homolog 2) forms mixed disulfides with the cysteine-rich intestinal glycoprotein MUC2 that forms the protective mucus gel lining the intestine (35). Each of these covalent chaperones is involved in oxidative protein folding in the endoplasmic reticulum (36). By contrast, YajL, which is located in the cytoplasm, forms mixed disulfide with many proteins upon oxidative stress and likely protects them against oxidative stress and aggregation, in accordance with its roles in oxidative stress resistance and protein solubilization (7).…”

ERp44 C160S/C212S mutants regulate IP3R1 channel activity

“…Luminal-side regulation has been proposed to involve conformational changes of IP 3 R that affect the channel activity (Thrower et al, 2000;Otsu et al, 2006). Another possibility is that the intermolecular disulfide bond causes conformational change and generates a new molecular surface of IP 3 R 1 that can function as a novel binding site for other regulating proteins (Kang et al, 2008;Cortini and Sitia, 2010). Some luminal factors, such as the redox potential, Ca 2+ (Higo et al, 2005;Kang et al, 2008) and Ero1α (Anelli et al, 2003;Li et al, 2009), have also been inferred to regulate IP 3 R by affecting the binding of ERp44 to the L3-1 loop of IP 3 R. Therefore, it is hard to exclude the possibility that the effect of luminal factors were altered by the formation of intermolecular disulfide bond between ERp44 and IP 3 R. Hence, further experiments are needed to evaluate the precise mechanisms.…”

“…The channel domain contains six transmembrane domains, and as a result there are three "loops" that reside in the ER lumen (Higo et al, 2005). The events occurring in the luminal domains of IP 3 Rs have attracted great concern, and some important progress has been made over the past several years (Anelli et al, 2003;Boehning et al, 2003;Marciniak et al, 2004;Higo et al, 2005;Li et al, 2009;Cortini and Sitia, 2010).…”

“…It has been reported that ERp44 affects calcium transient (Higo et al, 2005;Pan et al, 2011) and gene transcription (Pan et al, 2011) by binding to and inhibiting IP 3 receptor subtype 1 (IP 3 R 1 ). Capable of interacting with both Ero1α and IP 3 R 1 , ERp44 may function as a signal integrator to link redox and Ca 2+ signaling Cortini and Sitia, 2010;Higo et al, 2010). However, the mechanism by which ERp44 and its mutants regulate IP 3 R activity and Ca 2+ release remains unknown.…”