1. Beclin 2 negatively regulates innate immune signaling and tumor development.
- Author
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Zhu, Motao, Deng, Guangtong, Tan, Peng, Xing, Changsheng, Guan, Cuiping, Jiang, Chongming, Zhang, Yinlong, Ning, Bo, Li, Chaoran, Yin, Bingnan, Chen, Kaifu, Zhao, Yuliang, Wang, Helen Y, Levine, Beth, Nie, Guangjun, and Wang, Rong-Fu
- Subjects
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METABOLIC regulation , *THERAPEUTICS , *TUMORS , *POSTOPERATIVE nausea & vomiting , *BLADDER exstrophy - Abstract
Beclin 2 plays a critical role in metabolic regulation and obesity, but its functions in innate immune signaling and cancer development remain largely unknown. Here, we identified Beclin 2 as a critical negative regulator of inflammation and lymphoma development. Mice with homozygous ablation of BCL2-interacting protein 2 (Becn2) developed splenomegaly and lymphadenopathy and markedly increased ERK1/2 and NF-κB signaling for proinflammatory cytokine production. Beclin 2 targeted the key signaling kinases MEKK3 and TAK1 for degradation through an ATG9A-dependent, but ATG16L/Beclin 1/LC3-independent, autophagic pathway. Mechanistically, Beclin 2 recruited MEKK3 or TAK1 through ATG9A to form a complex (Beclin 2-ATG9A-MEKK3) on ATG9A+ vesicles upon ULK1 activation. Beclin 2 further interacted with STX5 and STX6 to promote the fusion of MEKK3- or TAK1-associated ATG9A+ vesicles to phagophores for subsequent degradation. Importantly, Becn2-deficient mice had a markedly increased incidence of lymphoma development, with persistent STAT3 activation. Myeloid-specific ablation of MEKK3 (Map3k3) completely rescued the phenotypes (splenomegaly, higher amounts of proinflammatory cytokines, and cancer incidence) of Becn2-deficient mice. Hence, our findings have identified an important role of Beclin 2 in the negative regulation of innate immune signaling and tumor development through an ATG9A-dependent, but ATG16L/Beclin 1/LC3-independent, autophagic pathway, thus providing a potential target for the treatment of inflammatory diseases and cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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