ABSTRACT

BECN2 (beclin 2) is a newly identified mammalian-specific macroautophagy/autophagy family member, and plays a critical role in the control of obesity and insulin sensitivity. However, its role in innate immune signaling and inflammation remains elusive. In our recent study, we show that BECN2 functions as a negative regulator in innate immune signaling and tumor development through non-canonical autophagy. Loss of Becn2 causes splenomegaly, lymphadenopathy, elevated proinflammatory cytokine production and spontaneous lymphoma development in mice. Mechanistically, BECN2 mediates the degradation of MAP3K7/TAK1 and MAP3K3/MEKK3 through an ATG9A- and ULK1-dependent but ATG16L1-BECN1-MAP1LC3B/LC3B-independent autophagy pathway to control systemic inflammation. BECN2 interacts with MAP3K7 and MAP3K3 through the engagement of ATG9A⁺ vesicles upon ULK1 activation, and promotes the fusion of MAP3K3- or MAP3K7-associated ATG9A⁺ vesicles with phagophores for subsequent degradation. Our findings have identified a previously unrecognized role of BECN2 in innate immune signaling and tumor development through non-canonical autophagy, thus providing a potential target for inflammatory disease and cancer therapy.

摘要

BECN2 (beclin 2) 是一种新发现的哺乳动物特异性巨自噬/自噬家族成员，在控制肥胖和胰岛素敏感性方面起着关键作用。然而，它在先天免疫信号和炎症中的作用仍然难以捉摸。在我们最近的研究中，我们表明 BECN2 通过非典型自噬在先天免疫信号传导和肿瘤发展中起负调节作用。Becn2的损失导致小鼠脾肿大、淋巴结肿大、促炎细胞因子产生增加和自发性淋巴瘤发展。从机制上讲，BECN2 通过依赖 ATG9A 和 ULK1 但不依赖 ATG16L1-BECN1-MAP1LC3B/LC3B 的自噬途径介导 MAP3K7/TAK1 和 MAP3K3/MEKK3 的降解，以控制全身炎症。BECN2在 ULK1 激活时通过 ATG9A ⁺囊泡的参与与 MAP3K7 和 MAP3K3 相互作用，并促进 MAP3K3 或 MAP3K7 相关的 ATG9A ⁺囊泡与吞噬细胞融合以进行后续降解。我们的研究结果已经确定了 BECN2 在先天免疫信号传导和肿瘤发展中通过非典型自噬发挥的先前未被认识的作用，从而为炎症疾病和癌症治疗提供了一个潜在的靶点。