Year: 2020
Type: article
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.
DOI: 10.1172/jci133283
Institutions: University of Southern California, Houston Methodist, USC Norris Comprehensive Cancer Center, National Center for Nanoscience and Technology, Central South University, Xiangya Hospital Central South University, Third People's Hospital of Hangzhou, Children's Hospital of Los Angeles, Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: G1736252752, CPRIT Core for RNA Therapeutics and Research, Identification of novel immune targets and neoantigens for development of immunotherapy for breast cancer, G5989595523, G7041654008, Immunotherapy targeting triple negative breast cancer using NY-ESO-1-specific TCRs and blockade of immune suppression, University of Southern California Norris Comprehensive Cancer Center Support Grant (CCSG)
OpenAlex ID: W3082611265