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Biology Articles » Biochemistry » Signaling the Unfolded Protein Response from the Endoplasmic Reticulum » Physiological Roles of the UPR

Physiological Roles of the UPR
- Signaling the Unfolded Protein Response from the Endoplasmic Reticulum

Physiological Roles of the UPR 

During cell growth, differentiation, and environmental stimuli there are different levels of protein folding load imposed upon the ER. Cells have evolved the ability to augment their folding capacity and remodel their secretory pathway in response to developmental demands and physiological changes. Accumulating evidence suggests that the UPR plays important roles in these processes. An excellent example is plasma cell differentiation. On terminal differentiation of B lymphoid cells to plasma cells, the ER compartment expands ~5-fold to accommodate the large increase in immunoglobulin synthesis (52). Interestingly, the UPR transcriptional activator XBP1 is required for plasma cell differentiation (53). XBP1-deficient B lymphoid cells express immunoglobulin genes and undergo isotype switching but are defective in plasma cell differentiation and do not secrete high levels of immunoglobulins. Expression of the spliced form of XBP1 efficiently restores production of secreted immunoglobulins in XBP1-deficient B cells, suggesting a physiological role for the UPR in high rate production of secreted antibodies (54). During plasma cell differentiation, IRE1-mediated splicing of XBP1 mRNA was found to depend on increased translation of immunoglobulin chains (5456). These observations support the hypothesis that increased synthesis of immunoglobulins produces greater amounts of nascent, unfolded, and unassembled subunits that bind and sequester BiP, leading to UPR activation. Indeed, BiP is the most abundantly expressed UPR-dependent gene and was first identified as encoding a protein that binds immunoglobulin heavy chains in the absence of light chains (57). However, the current studies do not exclude the possibility that the UPR may signal a B cell differentiation program that occurs prior to increased antibody synthesis. Although cleavage of ATF6 and splicing of XBP1 mRNA is observed during B cell differentiation, the activation and roles of IRE1a and PERK in differentiating B cells have yet to be directly investigated (55).

UPR signaling is also essential for maintaining glucose homeostasis. In this respect, it is interesting to note that the UPR was first characterized as transcriptional activation of a set of genes, encoding glucose-regulated proteins (GRPs), in response to glucose/energy deprivation (58). We now know that pancreatic b-cells uniquely require the UPR for survival during intermittent fluctuations in blood glucose (32, 59). Humans and mice with deletions in PERK have a profound pancreatic b-cell dysfunction and develop infancy-onset diabetes (59, 60). In addition, mice with a mutation at the eIF2a phosphorylation site display a severe b-cell dysfunction (59). A model showing that blood glucose levels influence the protein folding status in the ER of the b-cell has been proposed. As glucose levels decline, the energy supply decreases, so protein folding becomes inefficient in the ER and therefore activates the PERK-eIF2a subpathway of the UPR to attenuate protein translation. Conversely, as blood glucose levels rise, eIF2a would be dephosphorylated so that translation would accelerate to increase proinsulin synthesis (32). In addition, continual elevation in blood glucose, such as that which occurs during insulin resistance, would prolong proinsulin translation to overload the ER folding capacity and thereby activate the UPR. In this manner, a balance between glucose level and PERK-eIF2a UPR signaling is essential for regulated translation of insulin, b-cell function, and survival.

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