STING directly activates autophagy to tune the innate immune response.,Cell Death and Differentiation

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STING directly activates autophagy to tune the innate immune response.
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2018-12-19 , DOI: 10.1038/s41418-018-0251-z
Dong Liu _{1,

2} , Hao Wu ₁ , Chenguang Wang ₃ , Yanjun Li ₁ , Huabin Tian _{2,

4} , Sami Siraj _{1,

5} , Sheikh Arslan Sehgal _{1,

2} , Xiaohui Wang ₁ , Jun Wang ₁ , Yingli Shang ₆ , Zhengfan Jiang ₃ , Lei Liu ₁ , Quan Chen _{1,

2,

7}

Affiliation

STING (stimulator of interferon genes) is a central molecule that binds to cyclic dinucleotides produced by the cyclic GMP-AMP synthase (cGAS) to activate innate immunity against microbial infection. Here we report that STING harbors classic LC-3 interacting regions (LIRs) and mediates autophagy through its direct interaction with LC3. We observed that poly(dA:dT), cGAMP, and HSV-1 induced STING-dependent autophagy and degradation of STING immediately after TBK1 activation. STING induces non-canonical autophagy that is dependent on ATG5, whereas other autophagy regulators such as Beclin1, Atg9a, ULK1, and p62 are dispensable. LIR mutants of STING abolished its interaction with LC3 and its activation of autophagy. Also, mutants that abolish STING dimerization and cGAMP-binding diminished the STING-LC3 interaction and subsequent autophagy, suggesting that STING activation is indispensable for autophagy induction. Our results thus uncover dual functions of STING in activating the immune response and autophagy, and suggest that STING is involved in ensuring a measured innate immune response.

中文翻译：

STING直接激活自噬以调节先天免疫反应。

STING（干扰素基因的刺激物）是与环状GMP-AMP合酶（cGAS）产生的环状二核苷酸结合以激活针对微生物感染的先天免疫力的中心分子。在这里，我们报道STING拥有经典的LC-3相互作用区域（LIR），并通过与LC3的直接相互作用介导自噬。我们观察到，poly（dA：dT），cGAMP和HSV-1在TBK1激活后立即诱导STING依赖性自噬和STING降解。STING诱导依赖于ATG5的非典型自噬，而其他自噬调节剂如Beclin1，Atg9a，ULK1和p62则是可有可无的。STING的LIR突变体取消了它与LC3的相互作用以及自噬的激活。此外，取消STING二聚化和cGAMP结合的突变体也会减少STING-LC3相互作用和随后的自噬，提示STING激活对于自噬诱导是必不可少的。因此，我们的结果揭示了STING在激活免疫反应和自噬中的双重功能，并表明STING参与了确保测量的先天免疫反应的过程。

更新日期：2019-01-26

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