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Beclin 2 negatively regulates innate immune signaling and tumor development
- Source :
- Journal of Clinical Investigation. October, 2020, Vol. 130 Issue 10, p5349, 21 p.
- Publication Year :
- 2020
-
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-[kappa]B 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.sup.+] vesicles upon ULK1 activation. Beclin 2 further interacted with STX5 and STX6 to promote the fusion of MEKK3- or TAK1-associated [ATG9A.sup.+] 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 ATG9Adependent, but ATG16L/Beclin 1/LC3-independent, autophagic pathway, thus providing a potential target for the treatment of inflammatory diseases and cancer.<br />Introduction Autophagy is an essential cellular process for maintaining cell homeostasis and attenuating cell stresses through a 'self-eating' mechanism. Many autophagy-related (ATG) proteins have been identified as functioning in autophagy [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 130
- Issue :
- 10
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.637941294
- Full Text :
- https://doi.org/10.1172/JCI133283