PAX5 interacts with RIP2 to promote NF-κB activation and drug-resistance in B-lymphoproliferative disorders.
Paired box protein 5 (PAX5) plays a lineage determination role in B-cell development. However, high expression of PAX5 has been also found in various malignant diseases, including B-lymphoproliferative disorders (B-LPDs), but its functions and mechanisms in these diseases are still unclear. Here, we show that PAX5 induces drug resistance through association and activation of receptor-interacting serine/threonine-protein kinase 2 (RIP2; also known as RIPK2), and subsequent activation of NF-κB signaling and anti-apoptosis gene expression in B-lymphoproliferative cells. Furthermore, PAX5 is able to interact with RIP1 and RIP3, modulating both RIP1-mediated TNFR and RIP2-mediated NOD1 and NOD2 pathways. Our findings describe a new function of PAX5 in regulating RIP1 and RIP2 activation, which is at least involved in chemotherapeutic drug resistance in B-LPDs.
Key Laboratory of Innate Immunity and Chronic Disease of CAS, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Dong
D
Wang
Key Laboratory of Innate Immunity and Chronic Disease of CAS, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Jingyu
J
Chen
Key Laboratory of Innate Immunity and Chronic Disease of CAS, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Rui
R
Li
Department of Hematology, Anhui Provincial Hospital, 17 Lujiang Road, Hefei, Anhui Province 230001, China.
Guolin
G
Wu
Department of Hematology, Anhui Provincial Hospital, 17 Lujiang Road, Hefei, Anhui Province 230001, China.
Zimin
Z
Sun
Department of Hematology, The Second Hospital of Anhui Medical University, 678 Furong Road, Hefei, Anhui Province 230601, China.
Zhitao
Z
Wang
Department of Hematology, The Second Hospital of Anhui Medical University, 678 Furong Road, Hefei, Anhui Province 230601, China.
Zhimin
Z
Zhai
Key Laboratory of Innate Immunity and Chronic Disease of CAS, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Fang
F
Fang
Key Laboratory of Innate Immunity and Chronic Disease of CAS, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Yugang
Y
Guo
Key Laboratory of Innate Immunity and Chronic Disease of CAS, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Yongjun
Y
Zhong
Key Laboratory of Innate Immunity and Chronic Disease of CAS, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Ming
M
Jiang
Key Laboratory of Innate Immunity and Chronic Disease of CAS, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Huan
H
Xu
Key Laboratory of Innate Immunity and Chronic Disease of CAS, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Minhua
M
Chen
Key Laboratory of Innate Immunity and Chronic Disease of CAS, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Guodong
G
Shen
Key Laboratory of Innate Immunity and Chronic Disease of CAS, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Jie
J
Sun
Emergency Department, the First Hospital of Jilin University, Changchun 130021, China.
Bailing
B
Yan
Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Chundong
C
Yu
Key Laboratory of Innate Immunity and Chronic Disease of CAS, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Zhigang
Z
Tian
Key Laboratory of Innate Immunity and Chronic Disease of CAS, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China xiaow@ustc.edu.cn.
Weihua
0000-0001-9102-6326
W
Xiao
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D000069286:Bortezomib / Q000494:pharmacology / Q000627:therapeutic use; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000378:metabolism* / Q000473:pathology; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D053472:Nod Signaling Adaptor Proteins / Q000378:metabolism; D051757:PAX5 Transcription Factor / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000970:Antineoplastic Agents; D016328:NF-kappa B; D053472:Nod Signaling Adaptor Proteins; D051757:PAX5 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2
B-lymphoproliferative disorders; Drug resistance; NF-κB; PAX5; RIP2