The efficiency of cysteine‐mediated intracellular retention determines the differential fate of secretory IgA and IgM in B and plasma cells

Guenzi, Silvia; Fra, Annamaria; Sparvoli, Antonella; Bet, Paola; Rocco, Mattia; Sitia, Roberto

doi:10.1002/eji.1830241033

Cited by 44 publications

(37 citation statements)

References 33 publications

(10 reference statements)

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“…Functionally, the aggregation of PrP␣3M mutants suggests that CtmPrP may exert its toxic function through an oligomeric thiol trap. Such traps have been described in the regulation of IgM and adiponectin secretions (63)(64)(65)(66)(67)(68)(69). Importantly, given the validation of the PrP chains by the ER quality control systems the assembly of such oligomeric traps must take place upon delivery to a different environment (20).…”

Section: Discussionmentioning

confidence: 99%

Failure of Prion Protein Oxidative Folding Guides the Formation of Toxic Transmembrane Forms

Lisa

Domingo

Martínez

et al. 2012

Journal of Biological Chemistry

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Background:In vivo folding could play an essential role in prion neurodegenerations. Results: Artificial mutants causing labile PrP folds when expressed in cells originate toxic CtmPrP featured by the absence of the intramolecular disulfide bond. Conclusion: Oxidative folding impairment facilitates the formation of the toxic PrP forms. Significance: Unveiling the mechanism facilitating the formation of toxic PrP forms is crucial for the understanding and prevention of prion disorders.The mechanism by which pathogenic mutations in the globular domain of the cellular prion protein (PrP C ) increase the likelihood of misfolding and predispose to diseases is not yet known. Differences in the evidences provided by structural and metabolic studies of these mutants suggest that in vivo folding could be playing an essential role in their pathogenesis. To address this role, here we use the single or combined M206S and M213S artificial mutants causing labile folds and express them in cells. We find that these mutants are highly toxic, fold as transmembrane PrP, and lack the intramolecular disulfide bond. When the mutations are placed in a chain with impeded transmembrane PrP formation, toxicity is rescued. These results suggest that oxidative folding impairment, as on aging, can be fundamental for the genesis of intracellular neurotoxic intermediates key in prion neurodegenerations.Prion disorders are dominant gain-of-function neurodegenerations whose pathogenesis is linked to misfolded forms of the cellular prion protein (PrP C ), 3 including the prion PrP Sc and the neurotoxic CtmPrP (1-4). PrPSc is an aggregated and proteaseresistant ␤-sheet-enriched conformer of PrP C , which self-perpetuates by the templating the conversion of cell surface PrP C (1, 4). In contrast, CtmPrP is an intracellular transmembrane form generated at the ER with neurotoxic properties (1,5,6). Despite that CtmPrP formation was associated with features of the ER translocation process several pathogenic mutations in the C-terminal domain such as H187R and E200K enhance its levels, suggesting a yet unexplored in vivo interplay between folding and the accumulation and action of this neurotoxic form (6 -8).Since the enunciation of the prion hypothesis, research has focused on the mechanism by which a native PrP C structure reorganizes and acquires self-propagative features like those of PrP Sc (9 -11). The PrP C native state was assigned to the fold adopted by the chain lacking the signal sequences and containing the disulfide bond and used as reference for testing the effect of pathogenic mutations and its conversion into active prions (10,(12)(13)(14)(15)(16). However, the in vivo folding of proteins segregating into the secretory route such as PrP is a complex process participated by the ER folding machinery. This machinery coordinates processing (signal sequences removal, addition of covalent modifications, binding of cofactors, etc.), avoids undesired aggregations, and permits the acquisition of correct structure. This global process involves m...

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Section: Discussionmentioning

confidence: 99%

Failure of Prion Protein Oxidative Folding Guides the Formation of Toxic Transmembrane Forms

Lisa

Domingo

Martínez

et al. 2012

Journal of Biological Chemistry

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“…IgM is secreted by plasma cells only as pentamers containing a J chain or hexamers (20). This is due to the fact that the carboxylterminal cysteine of secretory ( s ) chains (Cys-575) serves as a three-way switch mediating the assembly, retention, and degradation of unpolymerized IgM subunits (21)(22)(23). For reasons that are still unclear, IgM polymerization is inefficient in B cells (24).…”

Section: The Endoplasmic Reticulum (Er)mentioning

confidence: 99%

Reduction of Interchain Disulfide Bonds Precedes the Dislocation of Ig-µ Chains from the Endoplasmic Reticulum to the Cytosol for Proteasomal Degradation

Fagioli¹,

Mezghrani²,

Sitia³

2001

Journal of Biological Chemistry

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Proteins that fail to fold or assemble in the endoplasmic reticulum (ER) are generally dislocated across the membrane to be degraded by cytosolic proteasomes. To investigate how the quality control machinery handles individual subunits that are part of covalent oligomers, we have analyzed the fate of transport-competent Ig light (L) chains that form disulfide bonds with shortlived heavy chains. When expressed alone, L chains are secreted. In cells producing excess , most L chains are retained in the ER as covalent ⅐L or 2 ⅐L 2 complexes. While chains present in these complexes are degraded by proteasomes, L chains are stable. Few L chains are secreted; most reassociate with newly synthesized chains. Therefore, interchain disulfide bonds are reduced in the ER lumen before the dislocation of chains in a site from which freed L chains can be rapidly reinserted in the assembly line. The ER can thus sustain the simultaneous formation and reduction of disulfide bonds.

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“…In mammalian cells, exposed Cys residues in the C-terminal region of the heavy chains of IgA and secretory IgM are recognized by ER quality control; as a result, in B lymphocytes tetramers are retained in this compartment (Sitia et al, 1990;Guenzi et al, 1994). The efficiency of this retention is both dependent on the stage of B cell development and the amino acid context surrounding the Cys.…”

Section: Slow and Inefficient Secretionmentioning

confidence: 99%

Assembly, Secretion, and Vacuolar Delivery of a Hybrid Immunoglobulin in Plants

et al. 2000

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Secretory immunoglobulin (Ig) A is a decameric Ig composed of four α-heavy chains, four light chains, a joining (J) chain, and a secretory component (SC). The heavy and light chains form two tetrameric Ig molecules that are joined by the J chain and associate with the SC. Expression of a secretory monoclonal antibody in tobacco (Nicotiana tabacum) has been described: this molecule (secretory IgA/G [SIgA/G]) was modified by having a hybrid heavy chain sequence consisting of IgG γ-chain domains linked to constant region domains of an IgA α-chain. In tobacco, about 70% of the protein assembles to its final, decameric structure. We show here that SIgA/G assembly and secretion are slow, with only approximately 10% of the newly synthesized molecules being secreted after 24 h and the bulk probably remaining in the endoplasmic reticulum. In addition, a proportion of SIgA/G is delivered to the vacuole as at least partially assembled molecules by a process that is blocked by the membrane traffic inhibitor brefeldin A. Neither the SC nor the J chain are responsible for vacuolar delivery, because IgA/G tetramers have the same fate. The parent IgG tetrameric molecule, containing wild-type γ-heavy chains, is instead secreted rapidly and efficiently. This strongly suggests that intracellular retention and vacuolar delivery of IgA/G is due to the α-domains present in the hybrid α/γ-heavy chains and indicates that the plant secretory system may partially deliver to the vacuole recombinant proteins expected to be secreted.

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The efficiency of cysteine‐mediated intracellular retention determines the differential fate of secretory IgA and IgM in B and plasma cells

Cited by 44 publications

References 33 publications

Failure of Prion Protein Oxidative Folding Guides the Formation of Toxic Transmembrane Forms

Failure of Prion Protein Oxidative Folding Guides the Formation of Toxic Transmembrane Forms

Reduction of Interchain Disulfide Bonds Precedes the Dislocation of Ig-µ Chains from the Endoplasmic Reticulum to the Cytosol for Proteasomal Degradation

Assembly, Secretion, and Vacuolar Delivery of a Hybrid Immunoglobulin in Plants

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