The ALPK1/TIFA/NF-κB axis links a bacterial carcinogen to R-loop-induced replication stress.
The ALPK1/TIFA/NF-κB axis links a bacterial carcinogen to R-loop-induced replication stress.
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DOI：
10.1038/s41467-020-18857-z
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发表时间：
2020-10-09
影响因子：
16.6
通讯作者：
Müller A
中科院分区：
文献类型：
--
作者：
Bauer M;Nascakova Z;Mihai AI;Cheng PF;Levesque MP;Lampart S;Hurwitz R;Pfannkuch L;Dobrovolna J;Jacobs M;Bartfeld S;Dohlman A;Shen X;Gall AA;Salama NR;Töpfer A;Weber A;Meyer TF;Janscak P;Müller A
胃上皮细胞暴露于细菌致癌物幽门螺杆菌会导致DNA双链断裂。在这里，我们表明，H。幽门螺杆菌诱导的DNA损伤在S期细胞中共转录发生，S期细胞通过ALPK 1/TIFA信号通路对脂多糖生物合成中间体β-ADP-庚糖进行先天免疫识别后激活NF-κB信号。DNA损伤依赖于双功能RfaE酶和H.幽门螺杆菌感染伴随着复制叉停滞，并且也可以在来源于胃类器官的原代细胞中观察到。重要的是，H。幽门螺杆菌诱导的复制应激和DNA损伤依赖于在S期期间感染细胞中由于β-ADP-庚糖/ALPK 1/TIFA/NF-κB信号传导而形成的共转录RNA/DNA杂合体（R环）的存在。H.幽门螺杆菌位于胃炎患者胃粘膜中的S期细胞附近。总之，我们的结果将细菌感染和NF-κ B驱动的先天免疫应答与R环依赖性复制应激和DNA损伤联系起来。已知细菌病原体幽门螺杆菌（Helicobacter pylori）能够在其靶细胞的基因组中诱导DNA双链断裂。在这里，我们表明，H。幽门螺杆菌诱导的DNA损伤和复制应激发生在S期细胞中，这是由ALPK 1/TIFA/NF-κB信号传导轴激活触发的R环介导的转录/复制冲突的结果。
Exposure of gastric epithelial cells to the bacterial carcinogen Helicobacter pylori causes DNA double strand breaks. Here, we show that H. pylori-induced DNA damage occurs co-transcriptionally in S-phase cells that activate NF-κB signaling upon innate immune recognition of the lipopolysaccharide biosynthetic intermediate β-ADP-heptose by the ALPK1/TIFA signaling pathway. DNA damage depends on the bi-functional RfaE enzyme and the Cag pathogenicity island of H. pylori, is accompanied by replication fork stalling and can be observed also in primary cells derived from gastric organoids. Importantly, H. pylori-induced replication stress and DNA damage depend on the presence of co-transcriptional RNA/DNA hybrids (R-loops) that form in infected cells during S-phase as a consequence of β-ADP-heptose/ ALPK1/TIFA/NF-κB signaling. H. pylori resides in close proximity to S-phase cells in the gastric mucosa of gastritis patients. Taken together, our results link bacterial infection and NF-κB-driven innate immune responses to R-loop-dependent replication stress and DNA damage. The bacterial pathogen Helicobacter pylori is known for its ability to induce DNA double-strand breaks in the genome of its target cells. Here, we show that H. pylori-induced DNA damage and replication stress occurs in S-phase cells as a result of R-loop-mediated transcription/replication conflicts that are triggered by activation of the ALPK1/TIFA/NF-κB signaling axis.
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影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
DOI：
10.1073/pnas.93.25.14648
发表时间：
1996-12-10
影响因子：
11.1
作者：
Censini, S;Lange, C;Covacci, A
通讯作者：
Covacci, A
影响因子：
4.5
作者：
Domínguez-Sánchez MS;Barroso S;Gómez-González B;Luna R;Aguilera A
通讯作者：
Aguilera A