Multipronged regulatory functions of a novel endonuclease (TieA) fromHelicobacter pylori

Abstract

Helicobacter pylori portrays a classical paradigm of persistent bacterial infections. A well balanced homeostasis of bacterial effector functions and host responses is purported to be the key in achieving long term colonization in specific hosts. H. pylori nucleases have been shown to assist in natural transformation, but their role in virulence and colonization remains elusive. Therefore, it is imperative to understand the involvement of these nucleases in the pathogenesis of H. pylori. Here, we report the multifaceted role of a TNFR-1 interacting endonuclease A (TieA) from H. pylori. tieA expression is differentially regulated in response to environmental stress and post adherence to gastric epithelial cells. Studies with isogenic knockouts of tieA revealed it to be a secretory protein which translocates into the host gastric epithelial cells independent of a type IV secretion system, gets phosphorylated by DNA-PK kinase and auto-phosphorylates as serine kinase. Furthermore, TieA binds to and cleaves DNA in a non-specific manner and promotes Fas mediated apoptosis in AGS cells. Additionally, TieA induced pro-inflammatory cytokine secretion via activation of transcription factor AP-1 and signaled through MAP kinase pathway. Collectively, TieA with its multipronged and moonlighting functions could facilitate H. pylori in maintaining a balance of bacterial adaptation, and elimination by the host responses.

Proteolytic Landscapes in Gastric Pathology and Cancerogenesis

“…Putative Target Importance Neoplastic Transformation, Proliferation, and Cell Survival ADAM9 and -15 gastric cancer cell lines proliferation [117] ADAM10 Notch1 [67] stem-like phenotype in cancer stem cells and supports anchorage independent growth [67] ADAM12 decreases gastric cancer cell lines proliferation [117] ADAM17 HB-EGF [53] Notch1 [67] reduces apoptosis [135], poor prognosis in gastric cancer [133], induces pro-survival signaling via the EGFR [44,135,136], cancer stem like phenotype, anchorage-independent growth [67] MMP7 (matrilysin-1) promotes proliferation in non-transformed epithelial cells [132] MMP12 (macrophage metalloelastase) inversely correlates with disease outcome [37,134] caspase-3 executioner caspase, activation by caspase-8, -9, or -10 [139], activation induced by H. pylori LPS and induced MMP9 [140], H. pylori induction of anti-apoptotic proteins of the cIAP family to reduce caspase-3-dependent apoptosis [141,142] caspase-8 initiator caspase, limited proteolytic (including autocatalytic) activity, engaged by death receptors, including tumor necrosis factor receptor 1 (TNFR1) and Fas/CD95 [139], TieA-protein-induced apoptosis [143] HtrA HtrA L171 variant was enriched in gastric cancer patients and may increase efficiency in basolateral CagA delivery by H pylori and risk for developing gastric cancer [59] Table 2. Cont.…”

“…H. pylori infection itself also interferes with pro- and anti-apoptotic pathways. For instance, H. pylori TieA protein induced gastric epithelial cell death via Fas- and caspase-8-mediated apoptosis [ 143 ]. Nevertheless, H. pylori utilizes numerous strategies to reduce caspase-3-dependent apoptosis in infected host cells, like the induction of anti-apoptotic proteins of the cIAP family [ 141 , 142 ].…”

Efficacy and safety of high-dose ilaprazole-amoxicillin dual therapy for Helicobacter pylori eradication: a prospective, single-center, randomized trial

“…Although the prevalence of H. pylori infection is declining in the developed countries, it remains a substantial cause of global morbidity and mortality (Sabari et al, 2017). Helicobacter pylori significantly contributes to a range of gastroduodenal diseases, including not only chronic gastritis and peptic ulcer disease, but also more serious conditions like mucosa-associated lymphoid tissue lymphoma and gastric cancer (Devi et al, 2016). In recognition of its carcinogenic potential, both the World Health Organization (WHO) in 1994 and the United States Department of Health and Human Services (HHS) in 2022 classified H. pylori as a group 1 or definite carcinogen (Zhu et al, 2017;Duan et al, 2023).…”