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The differential effects of dithiothreitol and 2-mercaptoethanol on the secretion of partially and completely assembled immunoglobulins suggest that thiol-mediated retention does not take place in or beyond the Golgi.
No full textRussell bodies as a model of ER storage diseases
No full textProtein accumulation represents the consequence of an altered cellular homeostasis leading to an imbalance between synthesis and disposal. Cells adopt a number of strategies to cope with this imbalance: through the Unfolded Protein Response (UPR), intracellular chaperons are increased to facilitate protein folding, and the Endoplasmic Reticulum (ER) expands to accommodate increased concentration of ER resident proteins. The induction of autophagy is also a strategy adopted to face the synthesis of aberrant proteins.
Our cellular model of protein accumulation regards mutant immunoglobulin: Ig-μ chain that lacks the first constant domain (μ∆CH1 chain). These aberrant chains can neither exit from, nor are efficiently degraded in the ER. As a consequence they accumulate generating dilated cisternae known as Russell bodies. Russell bodies are frequently detected in lymphoproliferative diseases, especially in disorders of secretory B cells.
Condensation of aberrant μ∆CH1 chains can occur in different sub-cellular locations: when Ig-L chains are produced detergent insoluble aggregates form in the rough ER; without L chains, aggregation occurs in ERGIC compartment.
We are interested to define whether and which cellular mechanisms are active or are impaired by the synthesis of aberrant Ig-μ chains assaying: i.e. ER stress, ER expansion, Autophagy modulation in our inducible cellular model (Hela-tet off) of Russell bodies formation. Our aim is to define if Russell bodies structures are a cell defence mechanism against proteotoxicit
Roles of N-glycans in the polymerization-dependent aggregation of mutant Ig-μ chains in the early secretory pathway
No full textThe polymeric structure of secretory IgM allows efficient antigen binding and complement fixation. The available structural models place the N-glycans bound to asparagines 402 and 563 of Ig-μ chains within a densely packed core of native IgM. These glycans are found in the high mannose state also in secreted IgM, suggesting that polymerization hinders them to Golgi processing enzymes. Their absence alters polymerization. Here we investigate their role following the fate of aggregation-prone mutant μ chains lacking the Cμ1 domain (μΔ). Our data reveal that μΔ lacking 563 glycans (μΔ5) form larger intracellular aggregates than μΔ and are not secreted. Like μΔ, they sequester ERGIC-53, a lectin previously shown to promote polymerization. In contrast, μΔ lacking 402 glycans (μΔ4) remain detergent soluble and accumulate in the ER, as does a double mutant devoid of both (μΔ4-5). These results suggest that the two C-terminal Ig-μ glycans shape the polymerization-dependent aggregation by engaging lectins and acting as spacers in the alignment of individual IgM subunits in native polymers
Russell bodies: a general response of secretory cells to synthesis of a mutant immunoglobulin which can neither exit from, nor be degraded in, the endoplasmic reticulum
No full text
ER storage diseases: a role for ERGIC-53 in controlling the formation and shape of Russell bodies.
No full textOwing to the impossibility of reaching the Golgi for secretion or the cytosol for
degradation, mutant Ig-mu chains that lack the first constant domain (muDeltaCH1)
accumulate as detergent-insoluble aggregates in dilated endoplasmic reticulum
cisternae, called Russell bodies. The presence of similar structures hallmarks
many ER storage diseases, but their pathogenic role(s) remain obscure. Exploiting
inducible cellular systems, we show here that Russell bodies form when the
synthesis of muDeltaCH1 exceeds the degradation capacity. Condensation occurs in
different sub-cellular locations, depending on the interacting molecules present
in the host cell: if Ig light chains are co-expressed, detergent-insoluble
muDeltaCH1-light chain oligomers accumulate in large ribosome-coated structures
(rough Russell bodies). In absence of light chains, instead, aggregation occurs
in smooth tubular vesicles and is controlled by N-glycan-dependent interactions
with ER-Golgi intermediate compartment 53 (ERGIC-53). In cells containing smooth
Russell bodies, ERGIC-53 co-localizes with muDeltaCH1 aggregates in a Ca2+
-dependent fashion. Our findings identify a novel ERGIC-53 substrate, and
indicate that interactions with light chains or ERGIC-53 seed muDeltaCH1
condensation in different stations of the early secretory pathway
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