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2018 Fiscal Year Final Research Report

The role of Bcl-xL in the formation of the Beclin 1 complex and induction of autophagy during bacterial infection

Research Project

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Project/Area Number 16K08775
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Bacteriology (including mycology)
Research InstitutionKyoto University

Principal Investigator

Aikawa Chihiro  京都大学, 医学研究科, 助教 (70725499)

Co-Investigator(Kenkyū-buntansha) 野澤 孝志  京都大学, 医学研究科, 助教 (10598858)
Project Period (FY) 2016-04-01 – 2019-03-31
Keywordsオートファジー / Group A Streptococcus / Beclin 1 / Bcl-xL / NLRX1
Outline of Final Research Achievements

Anti-apoptotic Bcl-2 family proteins are known to inhibit starvation-induced autophagy by directional interaction with Beclin 1, but how the interaction regulates anti-bacterial autophagy is still unclear. We found that Bcl-xL regulates Group A Streptococcus (GAS)-induced autophagy. Our data demonstrate that Bcl-xL but not Bcl-2 inhibits GAS-induced autophagy directly by suppressing autophagosome-lysosome fusion and indirectly by suppressing GAS internalization via interaction with Beclin 1-UVRAG.
We also demonstrate that NLRX1 functions as a negative regulator to inactivate the Beclin-UVRAG complex. GAS invasion was markedly increased in NLRX1 knockout cells, leading to the potentiation of autophagosome and autolysosome formation. This is induced by the interaction of NLRX1 with Beclin 1 and UVRAG. Furthermore, NLRX1 interacted with Beclin 1 via its NACHT domain and this interaction was responsible for the NLRX1-mediated inhibition of invasion and autophagic processes.

Free Research Field

細菌学

Academic Significance and Societal Importance of the Research Achievements

本研究から、Beclin 1によるオートファジー制御機構は、栄養飢餓時と細菌感染時でマシーナリーの一部に違いがあることが明らかになった。特に、細菌感染時には、Beclin 1自体はオートファゴソーム形成には関与せず、Bcl-xLやNLRX1といった分子との相互作用により細胞へと侵入する細菌数を制御することで、結果として形成されるオートファゴソームの数が増減することが明らかになった。この発見は細胞のもつオートファジーという細菌感染防御システムを深く理解する上で重要であると同時に、新たな感染治療法を構築する上でも、Beclin 1とその相互作用分子が優れた標的(対象)となることを示している。

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Published: 2020-03-30  

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