MOE Key Laboratory of Tropical Disease Control, Centre for Infection and Immunity Study (CIIS), School of Medicine, Sun Yat-sen University, Shenzhen, China.
The Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
EMBO Rep. 2023 Oct 9;24(10):e56948. doi: 10.15252/embr.202356948. Epub 2023 Sep 6.
The maintenance of lysosome homeostasis is crucial for cell growth. Lysosome-dependent degradation and metabolism sustain tumor cell survival. Here, we demonstrate that CCDC50 serves as a lysophagy receptor, promoting tumor progression and invasion by controlling lysosomal integrity and renewal. CCDC50 monitors lysosomal damage, recognizes galectin-3 and K63-linked polyubiquitination on damaged lysosomes, and specifically targets them for autophagy-dependent degradation. CCDC50 deficiency causes the accumulation of ruptured lysosomes, impaired autophagic flux, and superfluous reactive oxygen species, consequently leading to cell death and tumor suppression. CCDC50 expression is associated with malignancy, progression to metastasis, and poor overall survival in human melanoma. Targeting CCDC50 suppresses tumor growth and lung metastasis, and enhances the effect of BRAF inhibition. Thus, we demonstrate critical roles of CCDC50-mediated clearance of damaged lysosomes in supporting tumor growth, hereby identifying a potential therapeutic target of melanoma.
溶酶体稳态的维持对于细胞生长至关重要。溶酶体依赖性降解和代谢维持肿瘤细胞的存活。在这里，我们证明 CCDC50 作为溶酶体自噬受体，通过控制溶酶体完整性和更新来促进肿瘤的进展和侵袭。CCDC50 监测溶酶体损伤，识别损伤溶酶体上的半乳糖凝集素-3 和 K63 连接的多泛素化，并将其特异性靶向自噬依赖性降解。CCDC50 缺陷导致破裂的溶酶体积累、自噬流受损和过多的活性氧，从而导致细胞死亡和肿瘤抑制。CCDC50 的表达与人类黑色素瘤的恶性程度、转移进展和总体生存不良相关。靶向 CCDC50 可抑制肿瘤生长和肺转移，并增强 BRAF 抑制的效果。因此，我们证明了 CCDC50 介导的清除受损溶酶体在支持肿瘤生长中的关键作用，从而确定了黑色素瘤的一个潜在治疗靶点。
