Xbp1 Targets Canonical UPR and Non-canonical Pathways in Separate Tissues to Promote Longevity

Overview

Journal iScience

Publisher Cell Press

Date 2024 Jun 4

PMID 38832022

Authors

Mengjia Li

Haocheng Shou

Guillermo Martinez Corrales

Tatiana Svermova

Alessandra Vieira Franco

Nazif Alic

Affiliations

Soon will be listed here.

Abstract

Transcription factors can reprogram gene expression to promote longevity. Here, we investigate the role of Xbp1. Xbp1 is activated by splicing of its primary transcript, , to generate Xbp1, a key activator of the endoplasmic reticulum unfolded protein response (UPR). We show that Xbp1 induces the conical UPR in the gut, promoting longevity from the resident stem cells. In contrast, in the fat body, Xbp1 does not appear to trigger UPR but alters metabolic gene expression and is still able to extend lifespan. In the fat body, Xbp1 and dFOXO impinge on the same target genes, including the PGC-1α orthologue Srl, and requires to extend lifespan. Interestingly, unspliceable version of the mRNA, can also extend lifespan, hinting at roles in longevity for the poorly characterized Xbp1 transcription factor. These findings reveal the diverse functions of Xbp1 in longevity in the fruit fly.

References

Shimokawa I, Komatsu T, Hayashi N, Kim S, Kawata T, Park S . The life-extending effect of dietary restriction requires Foxo3 in mice. Aging Cell. 2015; 14(4):707-9. PMC: 4531086. DOI: 10.1111/acel.12340. View

Imanikia S, Sheng M, Castro C, Griffin J, Taylor R . XBP-1 Remodels Lipid Metabolism to Extend Longevity. Cell Rep. 2019; 28(3):581-589.e4. PMC: 6656787. DOI: 10.1016/j.celrep.2019.06.057. View

Wang L, Ryoo H, Qi Y, Jasper H . PERK Limits Drosophila Lifespan by Promoting Intestinal Stem Cell Proliferation in Response to ER Stress. PLoS Genet. 2015; 11(5):e1005220. PMC: 4422665. DOI: 10.1371/journal.pgen.1005220. View

Liang H, Ward W . PGC-1alpha: a key regulator of energy metabolism. Adv Physiol Educ. 2006; 30(4):145-51. DOI: 10.1152/advan.00052.2006. View

Deng Y, Wang Z, Gordillo R, Zhu Y, Ali A, Zhang C . Adipocyte Xbp1s overexpression drives uridine production and reduces obesity. Mol Metab. 2018; 11:1-17. PMC: 6001360. DOI: 10.1016/j.molmet.2018.02.013. View

Daitoku H, Yamagata K, Matsuzaki H, Hatta M, Fukamizu A . Regulation of PGC-1 promoter activity by protein kinase B and the forkhead transcription factor FKHR. Diabetes. 2003; 52(3):642-9. DOI: 10.2337/diabetes.52.3.642. View

Gutierrez E, Wiggins D, Fielding B, Gould A . Specialized hepatocyte-like cells regulate Drosophila lipid metabolism. Nature. 2006; 445(7125):275-80. DOI: 10.1038/nature05382. View

Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K . XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2002; 107(7):881-91. DOI: 10.1016/s0092-8674(01)00611-0. View

Henis-Korenblit S, Zhang P, Hansen M, McCormick M, Lee S, Cary M . Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity. Proc Natl Acad Sci U S A. 2010; 107(21):9730-5. PMC: 2906894. DOI: 10.1073/pnas.1002575107. View

10.

Tao R, Chen H, Gao C, Xue P, Yang F, Han J . Xbp1-mediated histone H4 deacetylation contributes to DNA double-strand break repair in yeast. Cell Res. 2011; 21(11):1619-33. PMC: 3364731. DOI: 10.1038/cr.2011.58. View

11.

Plongthongkum N, Kullawong N, Panyim S, Tirasophon W . Ire1 regulated XBP1 mRNA splicing is essential for the unfolded protein response (UPR) in Drosophila melanogaster. Biochem Biophys Res Commun. 2007; 354(3):789-94. DOI: 10.1016/j.bbrc.2007.01.056. View

12.

Ragheb R, Chuyen A, Torres M, Defaye A, Seyres D, Kremmer L . Interplay between trauma and Pseudomonas entomophila infection in flies: a central role of the JNK pathway and of CrebA. Sci Rep. 2017; 7(1):16222. PMC: 5701226. DOI: 10.1038/s41598-017-14969-7. View

13.

Rera M, Bahadorani S, Cho J, Koehler C, Ulgherait M, Hur J . Modulation of longevity and tissue homeostasis by the Drosophila PGC-1 homolog. Cell Metab. 2011; 14(5):623-34. PMC: 3238792. DOI: 10.1016/j.cmet.2011.09.013. View

14.

Zhao P, Huang P, Xu T, Xiang X, Sun Y, Liu J . Fat body Ire1 regulates lipid homeostasis through the Xbp1s-FoxO axis in . iScience. 2021; 24(8):102819. PMC: 8333185. DOI: 10.1016/j.isci.2021.102819. View

15.

Kishino A, Hayashi K, Hidai C, Masuda T, Nomura Y, Oshima T . XBP1-FoxO1 interaction regulates ER stress-induced autophagy in auditory cells. Sci Rep. 2017; 7(1):4442. PMC: 5493624. DOI: 10.1038/s41598-017-02960-1. View

16.

Dobson A, Boulton-McDonald R, Houchou L, Svermova T, Ren Z, Subrini J . Longevity is determined by ETS transcription factors in multiple tissues and diverse species. PLoS Genet. 2019; 15(7):e1008212. PMC: 6662994. DOI: 10.1371/journal.pgen.1008212. View

17.

Acosta-Alvear D, Zhou Y, Blais A, Tsikitis M, Lents N, Arias C . XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Mol Cell. 2007; 27(1):53-66. DOI: 10.1016/j.molcel.2007.06.011. View

18.

Lee A, Scapa E, Cohen D, Glimcher L . Regulation of hepatic lipogenesis by the transcription factor XBP1. Science. 2008; 320(5882):1492-6. PMC: 3620093. DOI: 10.1126/science.1158042. View

19.

Lopez-Otin C, Blasco M, Partridge L, Serrano M, Kroemer G . Hallmarks of aging: An expanding universe. Cell. 2023; 186(2):243-278. DOI: 10.1016/j.cell.2022.11.001. View

20.

Wen D, Gao Y, Wang J, Wang S, Zhong Q, Hou W . Role of muscle FOXO gene in exercise against the skeletal muscle and cardiac age-related defects and mortality caused by high-salt intake in Drosophila. Genes Nutr. 2023; 18(1):6. PMC: 10064743. DOI: 10.1186/s12263-023-00725-2. View