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The Pivotal Role of Erp44 in Patrolling Protein Secretion Tiziana Tempio1,2 and Tiziana Anelli1,2,*

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The Pivotal Role of Erp44 in Patrolling Protein Secretion Tiziana Tempio1,2 and Tiziana Anelli1,2,* © 2020. Published by The Company of Biologists Ltd | Journal of Cell Science (2020) 133, jcs240366. doi:10.1242/jcs.240366 REVIEW The pivotal role of ERp44 in patrolling protein secretion Tiziana Tempio1,2 and Tiziana Anelli1,2,* ABSTRACT et al., 2001; Pagani et al., 2000). Oxidized Ero1α recharges itself by Interactions between protein ligands and receptors are the main electron transfer to molecular oxygen (Tu and Weissman, 2002), language of intercellular communication; hence, how cells select which generates one molecule of H2O2 for every disulfide bond that is proteins to be secreted or presented on the plasma membrane is a formed in the nascent proteins. central concern in cell biology. A series of checkpoints are located The tenet of quality control (QC) is that only when a given step in along the secretory pathway, which ensure the fidelity of such protein their structural maturation process is complete can proteins move to signals (quality control). Proteins that pass the checkpoints operated downstream compartments. Two theories have been proposed to in the endoplasmic reticulum (ER) by the binding immunoglobulin explain the selectivity of protein secretion: cargo selection and bulk protein (BiP; also known as HSPA5 and GRP78) and the calnexin– flow. The first entails that export is promoted by cargo receptors, such – calreticulin systems, must still overcome additional scrutiny in the ER- as the lectins ER Golgi intermediate compartment (ERGIC) 53 kDa Golgi intermediate compartment (ERGIC) and the Golgi. One of the protein (ERGIC-53; also known as LMAN1), the ERGIC-53-like main players of this process in all metazoans is the ER-resident protein (ERGL; also known as LMAN1L) and the VIP-36-like protein 44 (ERp44); by cycling between the ER and the Golgi, ERp44 protein (VIPL; also known as LMAN2L) for glycoproteins (Breuza controls the localization of key enzymes designed to act in the ER but et al., 2004; Kwon et al., 2016; Neve et al., 2003; Nufer et al., 2003; that are devoid of suitable localization motifs. ERp44 also patrols the Yerushalmi et al., 2001; Zhang et al., 2009). According to the second secretion of correctly assembled disulfide-linked oligomeric proteins. model, proteins can proceed to downstream organelles unless Here, we discuss the mechanisms driving ERp44 substrate retained in, or retrieved to, a given compartment (Barlowe and recognition, with important consequences on the definition of ‘thiol- Helenius, 2016). mediated quality control’. We also describe how pH and zinc Bulk flow relies on the activity of QC systems to efficiently gradients regulate the functional cycle of ERp44, coupling quality recognize proteins that are not properly folded or assembled, to control and membrane trafficking along the early secretory prevent their transport (Fig. 1). In the ER, the same chaperones compartment. devoted to protein folding and maturation, such as the binding immunoglobulin protein (BiP; also known as HSPA5 and GRP78), KEY WORDS: ERp44, Protein folding, Quality control, Secretory calnexin (CNX; also known as CANX) and calreticulin (CRT; also pathway, Zinc known as CALR), act as controllers, recognizing hydrophobic stretches (Marcinowski et al., 2013) or sugar moieties (Tannous et al., Introduction 2015) in aberrant polypeptides (proximal QC). Additional QC steps Proteins that reside in the secretory pathway, as well as proteins occur in the ERGIC and in the Golgi (distal QC), in which the destined to traffic to the extracellular milieu or the plasma membrane, assembly of multimeric proteins is supervised (Anelli and Sitia, 2018; begin their journey in the endoplasmic reticulum (ER). There, they Shibuya et al., 2015; Sun and Brodsky, 2019). This QC mechanism undergo post-translational modifications, including N-glycosylation, was first described in 1990 to control the secretion of polymeric glycosylphosphatidylinositol (GPI) anchor addition and disulfide immunoglobulin M (IgM) (Fra et al., 1993; Sitia et al., 1990). A bond formation, which are controlled by specific enzymes (Braakman cysteine residue was shown to act as a three-way switch, mediating and Hebert, 2013). The insertion of disulfide bonds is crucial to the assembly, retention and degradation of unpolymerized subunits ensure the stability of polypeptides destined to the oxidizing (Fra et al., 1993). Post-ER QC steps also control the assembly of extracellular environment (Darby and Creighton, 1995). Certain multimeric receptors. Unassembled subunits of multimeric catalytic or allosteric disulfides also regulate protein function and membrane proteins, such as the major histocompatibility complex activity (Cook and Hogg, 2013). In mammalian cells, oxidative (MHC) class I and II, or the T-cell receptor are in fact recognized in folding is catalyzed by a large array of oxidoreductases belonging to the Golgi and retrieved to the ER (Dusseljee et al., 1998; Hughes the protein disulfide isomerase (PDI) family (Appenzeller-Herzog et al., 1997; Yamamoto et al., 2001) as a result of the activity of and Ellgaard, 2008). Most of these proteins have two cysteine different receptors (Briant et al., 2017; Yamasaki et al., 2014). residues in the active site (CXXC) that mediate disulfide interchange One of the main players in post-ER QC is the ER-resident protein reactions. When reduced, they act as reductases or isomerases; when 44 (ERp44) (Anelli et al., 2007). ERp44 belongs to the PDI protein oxidized, they transfer their disulfide bonds to nascent proteins family, although it has peculiar characteristics. First, it lacks the (Wang et al., 2015). In eukaryotic cells, the reduced PDI is recharged resolving cysteine residue in its active site (CRFS) (Anelli et al., primarily by the ER oxidoreductin 1 enzymes (Ero1α and Ero1β in 2002), a characteristic shared only with a few other PDI homologs, mammals) (Cabibbo et al., 2000; Frand and Kaiser, 1999; Mezghrani such as anterior gradient 2 (AGR2) and 3 (AGR3), and thioredoxin- related transmembrane protein 5 (TMX5; also known as 1Division of Genetics and Cell Biology, Vita-Salute San Raffaele University, TXNDC15); this excludes a role as a disulfide donor (Kozlov Milan 20132, Italy. 2IRCCS San Raffaele Scientific Institute, Milan 20132, Italy. et al., 2010), suggesting instead it could act as an isomerase. Second, and differently from most other family members, which reside in the *Author for correspondence ([email protected]) ER (reviewed in Hatahet and Ruddock, 2007), ERp44 is primarily T.A., 0000-0002-9159-9164 localized in the ERGIC and cis Golgi (Anelli et al., 2007). Journal of Cell Science 1 REVIEW Journal of Cell Science (2020) 133, jcs240366. doi:10.1242/jcs.240366 Endoplasmic reticulum ERES ERGIC Golgi Fig. 1. QC steps along the secretory Secretion pathway. The structure of the secretory pathway is perfectly suited for timing the different modifications that complex Folding proteins must undergo to attain their (i) native state. Monomeric proteins (blue oval) (i) can proceed to the Golgi only if they have reached their native status. Oligomeric proteins stabilized by non- Assembly covalent interactions or buried disulfides (blue and violet dimer) (ii) can reach the (ii) downstream compartments only if they Cargo are properly folded and assembled. enrichment These steps are supervised by the and selection proximal QC in the ER – unfolded at ERES SS SS (iii) SS proteins are thus retained and cannot SS SS SS Assembly SS HS SH SS leave the ER. Correctly folded proteins HS SH are enriched at ERES and transported to HS S H the ERGIC and the cis-Golgi. Some HS SSSH oligomeric soluble proteins, whose subunits are linked by exposed disulfide (iv) HSSSSS Stop SS HSSSSS bonds (orange ovals) (iii) undergo SH SS SH ERp44-dependent QC in post-ER compartments (distal QC). Likewise, some oligomeric transmembrane Assembly Transport proteins (light violet) (iv) are also to the PM scrutinized in post-ER compartments by distal QC, provided that all subunits Stop passed the proximal QC. It is not clear where protein oligomerization occurs, whether in the cis-Golgi or during the travel of the monomers from the ER to the Retain Retrieve Golgi. Only completely assembled structures can proceed and reach their Proximal QC: Distal QC: final destination; assembly intermediates correct folding and correct will be instead stopped and retrieved non-covalent assembly? oligomerization? to the ER. Key Transmembrane Oligomeric protein Monomeric protein Oligomeric protein protein subunit In this Review, we describe recent mechanistic evidence on how elegans (Box 1). This protein is abundant in professional secretory ERp44 escorts and regulates protein secretion, defining the set of cells (Human Protein Atlas) and its levels increase during B proteins derived from each cell that are secreted into the extracellular lymphocyte differentiation into plasma cells (van Anken et al., space (secretome), and at the same time controlling the composition 2003), concomitantly with the onset of IgM secretion. These results of the early exocytic organelles. In addition, we propose that ERp44 suggested that ERp44 could play a role in ER redox control, as it substrates can be grouped into clients, which are multimeric proteins covalently interacts with Ero1α (Anelli et al., 2002), as well as in that need the activity of ERp44 to be secreted in the correct protein folding, given it is overexpressed together with many other conformation, or partners, which in turn are ER-resident enzymes, folding enzymes during B to plasma cell differentiation
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