Helicobacter pylori pathogen inhibits cellular responses to oncogenic stress and apoptosis.
Animals
Antigens, Bacterial
/ genetics
Apoptosis
Bacterial Proteins
/ genetics
Carcinogenesis
/ metabolism
Gastric Mucosa
/ microbiology
Helicobacter Infections
/ microbiology
Helicobacter pylori
/ metabolism
Mice
Stomach Neoplasms
/ metabolism
Tumor Suppressor Protein p14ARF
/ metabolism
Ubiquitins
/ metabolism
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
received:
07
01
2022
accepted:
31
05
2022
entrez:
29
6
2022
pubmed:
30
6
2022
medline:
2
7
2022
Statut:
epublish
Résumé
Helicobacter pylori (H. pylori) is a common gastric pathogen that infects approximately half of the world's population. Infection with H. pylori can lead to diverse pathological conditions, including chronic gastritis, peptic ulcer disease, and cancer. The latter is the most severe consequence of H. pylori infection. According to epidemiological studies, gastric infection with H. pylori is the strongest known risk factor for non-cardia gastric cancer (GC), which remains one of the leading causes of cancer-related deaths worldwide. However, it still remains to be poorly understood how host-microbe interactions result in cancer development in the human stomach. Here we focus on the H. pylori bacterial factors that affect the host ubiquitin proteasome system. We investigated E3 ubiquitin ligases SIVA1 and ULF that regulate p14ARF (p19ARF in mice) tumor suppressor. ARF plays a key role in regulation of the oncogenic stress response and is frequently inhibited during GC progression. Expression of ARF, SIVA1 and ULF proteins were investigated in gastroids, H. pylori-infected mice and human gastric tissues. The role of the H. pylori type IV secretion system was assessed using various H. pylori isogenic mutants. Our studies demonstrated that H. pylori infection results in induction of ULF, decrease in SIVA1 protein levels, and subsequent ubiquitination and degradation of p14ARF tumor suppressor. Bacterial CagA protein was found to sequentially bind to SIVA1 and ULF proteins. This process is regulated by CagA protein phosphorylation at the EPIYA motifs. Downregulation of ARF protein leads to inhibition of cellular apoptosis and oncogenic stress response that may promote gastric carcinogenesis.
Identifiants
pubmed: 35767594
doi: 10.1371/journal.ppat.1010628
pii: PPATHOGENS-D-22-00028
pmc: PMC9242521
doi:
Substances chimiques
Antigens, Bacterial
0
Bacterial Proteins
0
Tumor Suppressor Protein p14ARF
0
Ubiquitins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1010628Subventions
Organisme : NCI NIH HHS
ID : R01 CA138833
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA206564
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK132710
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA116087
Pays : United States
Organisme : BLRD VA
ID : IK6 BX006300
Pays : United States
Organisme : BLRD VA
ID : I01 BX002115
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK058587
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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