Dataset Information

The specialized unfolded protein response of B lymphocytes: ATF6?-independent development of antibody-secreting B cells.

ABSTRACT: B lymphocytes, like all mammalian cells, are equipped with the unfolded protein response (UPR), a complex signaling system allowing for both pro- and mal-adaptive responses to increased demands on the endoplasmic reticulum (ER). The UPR is comprised of three signaling pathways initiated by the ER transmembrane stress sensors, IRE1?/?, PERK and ATF6?/?. Activation of IRE1 yields XBP1(S), a transcription factor that directs expansion of the ER and enhances protein biosynthetic and secretory machinery. XBP1(S) is essential for the differentiation of B lymphocytes into antibody-secreting cells. In contrast, the PERK pathway, a regulator of translation and transcription, is dispensable for the generation of antibody-secreting cells. Functioning as a transcription factor, ATF6? can augment ER quality control processes and drive ER expansion, but the potential role of this UPR pathway in activated B cells has not been investigated. Here, we report studies of ATF6?-deficient B cells demonstrating that ATF6? is not required for the development of antibody-secreting cells. Thus, when B cells are stimulated to secrete antibody, a specialized UPR relies exclusively on the IRE1-XBP1 pathway to remodel the ER and expand cellular secretory capacity.

SUBMITTER: Aragon IV

PROVIDER: S-EPMC3358488 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Publications

The specialized unfolded protein response of B lymphocytes: ATF6α-independent development of antibody-secreting B cells.

Aragon Ileana V IV Barrington Robert A RA Jackowski Suzanne S Mori Kazutoshi K Brewer Joseph W JW

Molecular immunology 20120501 3-4

B lymphocytes, like all mammalian cells, are equipped with the unfolded protein response (UPR), a complex signaling system allowing for both pro- and mal-adaptive responses to increased demands on the endoplasmic reticulum (ER). The UPR is comprised of three signaling pathways initiated by the ER transmembrane stress sensors, IRE1α/β, PERK and ATF6α/β. Activation of IRE1 yields XBP1(S), a transcription factor that directs expansion of the ER and enhances protein biosynthetic and secretory machin ...[more]

PMID: 22555069

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Project description:The Unfolded Protein Response (UPR) is a cascade of intracellular stress signaling from the endoplasmic reticulum (ER) that protect the cells from the stress caused by accumulation of unfolded or misfolded proteins in the ER. Activating transcription factor 6 (ATF6) is one of primary UPR transducers that remodels the stressed cells through transcriptional regulation. Although the activation mechanism and biological roles of ATF6 have been well studied, the understanding of the negative or feedback regulation of ATF6 remains elusive. In this report, we showed that ATF6 protein can be modified by small ubiquitin-like modification (SUMOylation) and that the transcriptional activity of ATF6 is negatively regulated by SUMOylation. We identified that SUMOylation of ATF6 is significantly increased in the cells expressing misfolded cystic fibrosis transmembrane conductance regulator (CFTR) encoded by the mutant human CFTR gene (dF508CFTR). Further analyses revealed two highly conserved SUMOylation motifs within the trans-activation domain of ATF6 protein of human, mouse, or rat specie. The human ATF6 protein can be SUMOylated mediated through the small ubiquitin-like modifier protein 1 (SUMO-1) and E3 SUMO-protein ligase 1 (PIAS1) at the conserved sumoylation residue Lys149 that is located at the N-terminal of the activated form of ATF6 protein. Bimolecular fluorescence complementation (BiFC) analysis confirmed that the activated ATF6 protein can be SUMOylated and that the ATF6 sumoylation occurs in the nuclei. Moreover, trans-activation reporter analysis demonstrated that SUMOylation of the ATF6 protein at the conserved residue Lys149 represses the transcriptional activity of ATF6. In summary, our study revealed a negative regulation of the UPR transducer ATF6 through post-translational SUMOylation. The information from this study will not only increase our understanding of the fine-tuning regulation of the UPR signaling but will also be informative to the modulation of the UPR for therapeutic benefits.

Dataset Information

The specialized unfolded protein response of B lymphocytes: ATF6?-independent development of antibody-secreting B cells.

Publications

The specialized unfolded protein response of B lymphocytes: ATF6α-independent development of antibody-secreting B cells.

Similar Datasets

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