Sam68 Contributes to Intestinal Inflammation in Experimental and Human Colitis

Overview

Journal Cell Mol Life Sci

Publisher Springer

Specialty Biology

Date 2021 Oct 25

PMID 34693458

Citations 5

Authors

Wendy A Goodman

Shrikanth C Basavarajappa

Angela R Liu

Franklin D Staback Rodriguez

Tailor Mathes

Parameswaran Ramakrishnan

Affiliations

Soon will be listed here.

Abstract

Sam68 is an RNA-binding protein with an adaptor role in signal transduction. Our previous work identified critical proinflammatory and apoptotic functions for Sam68, downstream of the TNF/TNFR1 and TLR2/3/4 pathways. Recent studies have shown elevated Sam68 in inflamed tissues from rheumatoid arthritis and ulcerative colitis (UC) patients, suggesting that Sam68 contributes to chronic inflammatory diseases. Here, we hypothesized that deletion of Sam68 is protective against experimental colitis in vivo, via reductions in TNF-associated inflammatory signaling. We used Sam68 knockout (KO) mice to study the role of Sam68 in experimental colitis, including its contributions to TNF-induced inflammatory gene expression in three-dimensional intestinal organoid cultures. We also studied the expression of Sam68 and inflammatory genes in colon tissues of UC patients. Sam68 KO mice treated with an acute course of DSS exhibited significantly less weight loss and histopathological inflammation compared to wild-type controls, suggesting that Sam68 contributes to experimental colitis. Bone marrow transplants showed no pathologic role for hematopoietic cell-specific Sam68, suggesting that non-hematopoietic Sam68 drives intestinal inflammation. Gene expression analyses showed that Sam68 deficiency reduced the expression of proinflammatory genes in colon tissues from DSS-treated mice, as well as TNF-treated three-dimensional colonic organoids. We also found that inflammatory genes, such as TNF, CCR2, CSF2, IL33 and CXCL10, as well as Sam68 protein, were upregulated in inflamed colon tissues of UC patients. This report identifies Sam68 as an important inflammatory driver in response to intestinal epithelial damage, suggesting that targeting Sam68 may hold promise to treat UC patients.

Citing Articles

SAM68 directs STING signaling to apoptosis in macrophages.

van der Horst D, Kurmasheva N, Marqvorsen M, Assil S, Rahimic A, Kollmann C Commun Biol. 2024; 7(1):283.

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Role of Sam68 as an adaptor protein in inflammatory signaling.

Gowd V, Kass J, Sarkar N, Ramakrishnan P Cell Mol Life Sci. 2024; 81(1):89.

PMID: 38351330 PMC: 10864426. DOI: 10.1007/s00018-023-05108-9.

Challenges and opportunities in inflammatory bowel disease: from current therapeutic strategies to organoid-based models.

Kong L, Chen S, Huang S, Zheng A, Gao S, Ye J Inflamm Res. 2024; 73(4):541-562.

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Sam68 is a druggable vulnerability point in cancer stem cells.

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References

de Souza H, Fiocchi C, Iliopoulos D . The IBD interactome: an integrated view of aetiology, pathogenesis and therapy. Nat Rev Gastroenterol Hepatol. 2017; 14(12):739-749. DOI: 10.1038/nrgastro.2017.110. View

Goodman W, Erkkila I, Pizarro T . Sex matters: impact on pathogenesis, presentation and treatment of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2020; 17(12):740-754. PMC: 7750031. DOI: 10.1038/s41575-020-0354-0. View

Neurath M . Current and emerging therapeutic targets for IBD. Nat Rev Gastroenterol Hepatol. 2017; 14(5):269-278. DOI: 10.1038/nrgastro.2016.208. View

DHaens G . Risks and benefits of biologic therapy for inflammatory bowel diseases. Gut. 2007; 56(5):725-32. PMC: 1942157. DOI: 10.1136/gut.2006.103564. View

Leppkes M, Roulis M, Neurath M, Kollias G, Becker C . Pleiotropic functions of TNF-α in the regulation of the intestinal epithelial response to inflammation. Int Immunol. 2014; 26(9):509-15. DOI: 10.1093/intimm/dxu051. View

Lu Y, Li X, Liu S, Zhang Y, Zhang D . Toll-like Receptors and Inflammatory Bowel Disease. Front Immunol. 2018; 9:72. PMC: 5797585. DOI: 10.3389/fimmu.2018.00072. View

Papadakis K, Targan S . Role of cytokines in the pathogenesis of inflammatory bowel disease. Annu Rev Med. 2000; 51:289-98. DOI: 10.1146/annurev.med.51.1.289. View

Locksley R, Killeen N, Lenardo M . The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. 2001; 104(4):487-501. DOI: 10.1016/s0092-8674(01)00237-9. View

Bradley J . TNF-mediated inflammatory disease. J Pathol. 2007; 214(2):149-60. DOI: 10.1002/path.2287. View

10.

Lukong K, Richard S . Sam68, the KH domain-containing superSTAR. Biochim Biophys Acta. 2003; 1653(2):73-86. DOI: 10.1016/j.bbcan.2003.09.001. View

11.

Ramakrishnan P, Baltimore D . Sam68 is required for both NF-κB activation and apoptosis signaling by the TNF receptor. Mol Cell. 2011; 43(2):167-79. PMC: 3142289. DOI: 10.1016/j.molcel.2011.05.007. View

12.

Tomalka J, de Jesus T, Ramakrishnan P . Sam68 is a regulator of Toll-like receptor signaling. Cell Mol Immunol. 2016; 14(1):107-117. PMC: 5214940. DOI: 10.1038/cmi.2016.32. View

13.

Fusaki N, Iwamatsu A, Iwashima M, Fujisawa J . Interaction between Sam68 and Src family tyrosine kinases, Fyn and Lck, in T cell receptor signaling. J Biol Chem. 1997; 272(10):6214-9. DOI: 10.1074/jbc.272.10.6214. View

14.

Frisone P, Pradella D, Di Matteo A, Belloni E, Ghigna C, Paronetto M . SAM68: Signal Transduction and RNA Metabolism in Human Cancer. Biomed Res Int. 2015; 2015:528954. PMC: 4529925. DOI: 10.1155/2015/528954. View

15.

Busa R, Paronetto M, Farini D, Pierantozzi E, Botti F, Angelini D . The RNA-binding protein Sam68 contributes to proliferation and survival of human prostate cancer cells. Oncogene. 2007; 26(30):4372-82. DOI: 10.1038/sj.onc.1210224. View

16.

Fu K, Sun X, Wier E, Hodgson A, Liu Y, Sears C . Sam68/KHDRBS1 is critical for colon tumorigenesis by regulating genotoxic stress-induced NF-κB activation. Elife. 2016; 5. PMC: 4959885. DOI: 10.7554/eLife.15018. View

17.

Qian J, Zhao W, Miao X, Li L, Zhang D . Sam68 modulates apoptosis of intestinal epithelial cells via mediating NF-κB activation in ulcerative colitis. Mol Immunol. 2016; 75:48-59. DOI: 10.1016/j.molimm.2016.05.011. View

18.

Sun W, Qin R, Qin R, Wang R, Ding D, Yu Z . Sam68 Promotes Invasion, Migration, and Proliferation of Fibroblast-like Synoviocytes by Enhancing the NF-κB/P65 Pathway in Rheumatoid Arthritis. Inflammation. 2018; 41(5):1661-1670. DOI: 10.1007/s10753-018-0809-4. View

19.

Sato T, van Es J, Snippert H, Stange D, Vries R, van den Born M . Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature. 2010; 469(7330):415-8. PMC: 3547360. DOI: 10.1038/nature09637. View

20.

de Jesus T, Ramakrishnan P . NF-κB c-Rel Dictates the Inflammatory Threshold by Acting as a Transcriptional Repressor. iScience. 2020; 23(3):100876. PMC: 7031323. DOI: 10.1016/j.isci.2020.100876. View