The Ben May Department for Cancer Research, The University of Chicago, Chicago, USA.
The Committee on Cancer Biology, The University of Chicago, Chicago, USA.
Sci Rep. 2021 Oct 15;11(1):20526. doi: 10.1038/s41598-021-00170-4.
UNC51-like kinase-1 (ULK1) is the catalytic component of the autophagy pre-initiation complex that stimulates autophagy via phosphorylation of ATG14, BECLN1 and other autophagy proteins. ULK1 has also been shown to specifically promote mitophagy but the mechanistic basis of how has remained unclear. Here we show that ULK1 phosphorylates the BNIP3 mitochondrial cargo receptor on a critical serine residue (S17) adjacent to its amino terminal LIR motif. ULK1 similarly phosphorylates BNIP3L on S35. Phosphorylation of BNIP3 on S17 by ULK1 promotes interaction with LC3 and mitophagy. ULK1 interaction also promotes BNIP3 protein stability by limiting its turnover at the proteasome. The ability of ULK1 to regulate BNIP3 protein stability depends on an intact "BH3" domain and deletion of its "BH3" domain reduces BNIP3 turnover and increases BNIP3 protein levels independent of ULK1. In summary ULK1 promotes mitophagy by both stabilization of BNIP3 protein and via phosphorylation of S17 to stimulate interaction with LC3.
UNC51 样激酶 1（ULK1）是自噬起始复合物的催化亚基，通过磷酸化 ATG14、BECLN1 和其他自噬蛋白来刺激自噬。ULK1 也被证明可以特异性地促进线粒体自噬，但其中的机制仍不清楚。在这里，我们发现 ULK1 在其氨基末端 LIR 基序附近的关键丝氨酸残基（S17）上磷酸化 BNIP3 线粒体货物受体。ULK1 同样在 S35 上磷酸化 BNIP3L。ULK1 对 BNIP3 上 S17 的磷酸化促进与 LC3 的相互作用，并诱导线粒体自噬。ULK1 相互作用还通过限制其在蛋白酶体中的周转率来促进 BNIP3 蛋白的稳定性。ULK1 调节 BNIP3 蛋白稳定性的能力依赖于完整的“BH3”结构域，而其“BH3”结构域的缺失会减少 BNIP3 的周转率并增加 BNIP3 蛋白水平，而与 ULK1 无关。总之，ULK1 通过 BNIP3 蛋白的稳定化以及通过磷酸化 S17 来刺激与 LC3 的相互作用来促进线粒体自噬。
