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Helicobacter Pylori: Preying on SIVA for Survival in the Stomach

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Helicobacter Pylori: Preying on SIVA for Survival in the Stomach The Journal of Clinical Investigation COMMENTARY Helicobacter pylori: preying on SIVA for survival in the stomach José B. Sáenz1 and Jason C. Mills1,2,3 1Division of Gastroenterology, Department of Internal Medicine, 2Department of Developmental Biology, and 3Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA. infected with cagA-positive strains of H. pylori showed increased XIAP phosphor- Infection with the Gram-negative bacterium Helicobacter pylori remains the ylation (the activated form of the protein) most important modifiable risk factor for the development of gastric cancer, and decreased SIVA1 compared with unin- a leading cause of cancer-related deaths worldwide. How the interactions fected individuals or those infected with between H. pylori and its host shape the gastric environment during chronic cagA-negative strains (5). This article thus infection warrants further investigation. In this issue of the JCI, Palrasu identifies yet another key function of the et al. used human cell lines and mouse models to provide mechanistic versatile CagA protein (10), in this case insight into H. pylori’s ability to delay apoptosis in gastric epithelial cells promoting H. pylori pathogenesis by sub- by actively driving the degradation of a proapoptotic factor, SIVA1. Their verting established host apoptotic defense findings suggest that promoting the survival of gastric epithelial cells has mechanisms (5). implications not only for H. pylori pathogenesis but for host tumorigenesis. Apoptosis in the stomach The Palrasu et al. study (5) forces us to reconsider the evolutionary tit-for-tat that exists between H. pylori and the human Helicobacter pylori overcomes changes in epithelial cell proliferation, stomach. H. pylori colonizes the stomach a myriad of host defense differentiation, and survival (3, 4). predominantly as an extracellular patho- mechanisms In this issue of the JCI, Palrasu et al. gen (11), so what would be the benefit to H. pylori is one of the most prolific human (5) provide detailed, mechanistic evi- the bacterium in delaying apoptosis and pathogens, affecting approximately half dence to illustrate one method by which promoting the survival of epithelial cells of the global population (1). The success H. pylori hijacks arguably the most basic, in which it does not primarily reside? One of H. pylori as a chronic pathogen relies innate epithelial defense, apoptosis. The possibility is that these host epithelial in large part on its ability to colonize and authors demonstrated that H. pylori infec- cells contribute to a mucinous, extracellu- persist within the hostile gastric environ- tion of human gastric epithelial cells led lar matrix that provides attachment sites ment by overcoming a myriad of host to downregulation of the proapoptotic for H. pylori as well as shelters the bacteria defense mechanisms, including peristal- factor, SIVA1 (5). SIVA1 promotes CD27- from the highly acidic gastric lumen (12). sis and, most notably, stomach acid. Like and T cell receptor–mediated apoptosis Apoptosis remains an effective means for other chronic pathogens, H. pylori has and inhibits Bcl-x(L) antiapoptotic activity the host to discard these harboring cells fine-tuned its interactions with its host, during cellular stress (6–8). Specifically, and limit H. pylori’s epithelial foothold. sufficiently modifying its environment to H. pylori infection promoted the proteaso- H. pylori, not to be outdone, might have survive, yet tempering activation of the mal degradation of SIVA1 by activating a developed its own arsenal to specifically host inflammatory response to persist. As ubiquitin ligase and X-linked inhibitor of overcome apoptosis and enhance its col- a result of alterations in host homeostasis, apoptosis, XIAP. Importantly, H. pylori’s onization. In addition to blocking apopto- H. pylori increases oncogenic risk, with antiapoptotic effects through SIVA1 are sis, a previous study showed that H. pylori H. pylori infection being the single most mediated by CagA, an H. pylori–specific also relies on CagA to promote and main- important factor for the development virulence factor that is delivered into host tain a proliferative state that enhances of gastric cancer (2). H. pylori–derived cells by a type IV secretion system and colonization (13). virulence factors increase cancer risk by that influences multiple host intracellu- From the host perspective, apoptosis inducing chronic, recurrent inflamma- lar processes (9). CagA directly regulates in the stomach serves a critical function tion while undermining intracellular host SIVA1 stability in vitro by stimulating its beyond simply restraining bacterial col- defense mechanisms and actively driving degradation. Accordingly, individuals onization. Apoptosis clears injured epi- thelial cells and limits ongoing cellular damage, which may be critical because H. Related Article: p. 2422 pylori infection produces a characteristic genotoxicity, with DNA damage at specific Conflict of interest: The authors have declared that no conflict of interest exists. Copyright: © 2020, American Society for Clinical Investigation. regions in the host genome, namely in Reference information: J Clin Invest. 2020;130(5):2183–2185. https://doi.org/10.1172/JCI135508. transcribed regions and proximal to telo- jci.org Volume 130 Number 5 May 2020 2183 COMMENTARY The Journal of Clinical Investigation meres (14). H. pylori has also been shown to proliferative, metaplastic cells (20). Down- F, Franceschi S. Global burden of cancers attrib- inhibit host DNA repair mechanisms (15). regulation of chief cell–specific SIVA1, utable to infections in 2012: a synthetic analysis. In addition to DNA damage, persistent therefore, could promote the survival of Lancet Glob Health. 2016;4(9):e609–e616. 3. Amieva M, Peek RM. Pathobiology of Helico- injury to gastric epithelial cells results in chief cells, representing one method by bacter pylori-induced gastric cancer. Gastroen- repeated rounds of cellular reorganiza- which H. pylori might increase oncogenic terology. 2016;150(1):64–78. tion and proliferation, as part of an innate risk, since long-lived chief cells are prone 4. Franco AT, et al. Regulation of gastric carcino- and conserved intracellular response to to cyclical reprogramming events that can genesis by Helicobacter pylori virulence factors. repair the gland (16). With each round of lead to chronic accumulation of DNA dam- Cancer Res. 2008;68(2):379–387. 5. Palrasu M, et al. Bacterial CagA protein proliferation, these metaplastic cells can age and an increased potential for neoplas- compromises tumor suppressor mecha- accumulate mutations that can predispose tic transformation (17, 20). Moreover, the nisms in gastric epithelial cells. J Clin Invest. to the development of cancer. H. pylori reprogramming of chief cells promotes H. 2020;130(5):2422–2434. could directly contribute to this cyclical pylori’s chronic colonization and expan- 6. Prasad KV, et al. CD27, a member of the tumor hit model of tumorigenesis (17) by promot- sion throughout the stomach (21). necrosis factor receptor family, induces apoptosis and binds to Siva, a proapoptotic protein. ing survival of metaplastic cells harboring While this study by Palrasu et al. impli- Proc Natl Acad Sci U S A. 1997;94(12):6346–6351. DNA damage or, specifically, mutations in cates SIVA1 as a critical component of H. 7. Xue L, et al. Siva-1 binds to and inhibits key growth or differentiation-regulating pylori pathogenesis and as a key check- BCL-X(L)-mediated protection against UV genes. The authors show that the effect of point in the progression to gastric cancer radiation-induced apoptosis. Proc Natl Acad Sci H. pylori on SIVA1 actively limits the host following chronic H. pylori infection (5), U S A. 2002;99(10):6925–6930. 8. Chu F, et al. The Siva-1 putative amphipathic response to DNA damage, independently questions remain. Does the degradation helical region (SAH) is sufficient to bind to BCL- of a critical regulator of the DNA damage of SIVA1 mark the evolution toward a pre- XL and sensitize cells to UV radiation induced response, p53 (18). Taken together, Palrasu neoplastic state during chronic H. pylori apoptosis. Apoptosis. 2004;9(1):83–95. et al. (5) lend further support for H. pylori’s infection? Can decreased SIVA1 levels 9. Odenbreit S, Püls J, Sedlmaier B, Gerland carcinogenic potential (19) through the portend a poorer prognosis in patients E, Fischer W, Haas R. Translocation of Helicobacter pylori CagA into gastric epi- CagA-mediated downregulation of apop- chronically infected with H. pylori? What thelial cells by type IV secretion. Science. totic mechanisms that would otherwise is the mutational burden in cells that have 2000;287(5457):1497–1500. weed out mutant cells. degraded SIVA1? What is the ultimate fate 10. Hatakeyama M. Helicobacter pylori CagA of these cells, and are other host mecha- and gastric cancer: a paradigm for hit- Chronic H. pylori infection nisms in place to trigger apoptosis in the and-run carcinogenesis. Cell Host Microbe. 2014;15(3):306–316. face of decreased SIVA1 levels? This study downregulates SIVA1 11. Dubois A, Borén T. Helicobacter pylori is inva- expression prompts a deeper understanding into the sive and it may be a facultative intracellular While Palrasu and colleagues primarily complex but critical host and microbial organism. Cell Microbiol. 2007;9(5):1108–1116. focused on H. pylori’s effects on SIVA1 in a mechanisms that regulate
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