Beclin 2 negatively regulates innate immune signaling and tumor development

• Published in: The Journal of clinical investigation 2020-10, Vol.130 (10), p.5349-5369
• Main Authors: 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, Wang, Rong-Fu
• Format: Article
• Language: English
• Subjects: Ablation; Animals; Autophagy; Autophagy - genetics; Autophagy - immunology; B cells; Biomedical research; Cancer; Carcinogenesis - genetics; Carcinogenesis - immunology; Cytokines; Cytokines - biosynthesis; Development and progression; Extracellular signal-regulated kinase; HEK293 Cells; Humans; Immunity, Innate - genetics; Inflammation; Inflammation Mediators - metabolism; Inflammatory diseases; Intracellular Signaling Peptides and Proteins - deficiency; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - physiology; Kinases; Ligands; Lymphadenopathy; Lymphadenopathy - etiology; Lymphadenopathy - genetics; Lymphadenopathy - immunology; Lymphatic system; Lymphocytes; Lymphoma; MAP Kinase Signaling System - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; NF-kappa B - metabolism; NF-κB protein; Non-Hodgkin's lymphomas; Obesity; Phenotypes; Physiology; Proteins; Rodents; Signal transduction; Signal Transduction - genetics; Signal Transduction - immunology; Splenomegaly; Splenomegaly - etiology; Splenomegaly - genetics; Splenomegaly - immunology; Stat3 protein; TAK1 protein; Thymus gland; Vesicles
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI133283

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.