Targeting the Lysosomal Degradation of Rab22a-NeoF1 Fusion Protein for Osteosarcoma Lung Metastasis.
Targeting the Lysosomal Degradation of Rab22a-NeoF1 Fusion Protein for Osteosarcoma Lung Metastasis.
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DOI：
10.1002/advs.202205483
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发表时间：
2023-02
期刊：
影响因子：
15.1
通讯作者：
Liao, Dan
中科院分区：
文献类型：
--
作者：
Zeng, Cuiling;Zhong, Li;Liu, Wenqiang;Zhang, Yu;Yu, Xinhao;Wang, Xin;Zhang, Ruhua;Kang, Tiebang;Liao, Dan
Rab22a - NeoF融合蛋白最近被报道为骨肉瘤肺转移的一个有前景的靶点。然而，这种融合蛋白在细胞中是如何被调控的仍不清楚。在此，通过多种筛选方法，研究发现Rab22a - NeoF1融合蛋白可被E3泛素连接酶STUB1经自噬受体NDP52介导的溶酶体途径降解，而这一过程由PINK1激酶促进。从机制上讲，STUB1催化Rab22a - NeoF1第112位赖氨酸上K63连接的泛素链形成，这使得Rab22a - NeoF1能够与NDP52结合，从而导致Rab22a - NeoF1的溶酶体降解。PINK1能够使Rab22a - NeoF1第120位丝氨酸发生磷酸化，进而促进Rab22a - NeoF1的泛素化和降解。与此一致的是，索拉非尼和瑞戈非尼可通过上调PINK1来抑制Rab22a - NeoF1诱导的骨肉瘤肺转移。这些发现表明，Rab22a - NeoF1融合蛋白的溶酶体降解可作为骨肉瘤肺转移的一个可靶向环节，这意味着索拉非尼和瑞戈非尼可能使RAB22A - NeoF1融合基因阳性的癌症患者受益。
在骨肉瘤细胞中，Rab22a - NeoF1融合蛋白可在第112位赖氨酸处通过K63连接的泛素链发生多聚泛素化，随后被自噬受体NDP52识别，从而导致Rab22a - NeoF1的溶酶体降解。这一过程由PINK1激酶通过使Rab22a - NeoF1第120位丝氨酸磷酸化来促进，而索拉非尼和瑞戈非尼可通过上调PINK1来减少Rab22a - NeoF1诱导的骨肉瘤肺转移。
Rab22a‐NeoF fusion protein has recently been reported as a promising target for osteosarcoma lung metastasis. However, how this fusion protein is regulated in cells remains unknown. Here, using multiple screenings, it is reported that Rab22a‐NeoF1 fusion protein is degraded by an E3 ligase STUB1 via the autophagy receptor NDP52‐mediated lysosome pathway, which is facilitated by PINK1 kinase. Mechanistically, STUB1 catalyzes the K63‐linked ubiquitin chains on lysine112 of Rab22a‐NeoF1, which is responsible for the binding of Rab22a‐NeoF1 to NDP52, resulting in lysosomal degradation of Rab22a‐NeoF1. PINK1 is able to phosphorylate Rab22a‐NeoF1 at serine120, which promotes ubiquitination and degradation of Rab22a‐NeoF1. Consistently, by upregulating PINK1, Sorafenib and Regorafenib can inhibit osteosarcoma lung metastasis induced by Rab22a‐NeoF1. These findings reveal that the lysosomal degradation of Rab22a‐NeoF1 fusion protein is targetable for osteosarcoma lung metastasis, proposing that Sorafenib and Regorafenib may benefit cancer patients who are positive for the RAB22A‐NeoF1 fusion gene. In osteosarcoma cells, Rab22a‐NeoF1 fusion protein can be polyubiquitinated at lysine112 via the K63‐linked ubiquitin chains and then be recognized by autophagy receptor NDP52, leading to the lysosomal degradation of Rab22a‐NeoF1. This process is promoted by PINK1 kinase via phosphorylating Rab22a‐NeoF1 at serine120, and Sorafenib and Regorafenib can diminish osteosarcoma lung metastasis induced by Rab22a‐NeoF1 through upregulating PINK1.
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