Ubiquitination of MAP1LC3B by pVHL is associated with autophagy and cell death in renal cell carcinoma.,Cell Death & Disease

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Ubiquitination of MAP1LC3B by pVHL is associated with autophagy and cell death in renal cell carcinoma.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-03-22 , DOI: 10.1038/s41419-019-1520-6
Hyun Mi Kang ₁ , Kyung Hee Noh ₁ , Tae Kyung Chang ₁ , Dongmin Park ₁ , Hyun-Soo Cho _{1,

2} , Jung Hwa Lim ₁ , Cho-Rok Jung _{1,

2}

Affiliation

Von Hippel Lindau (VHL) expression is significantly decreased in high-grade RCC, and autophagy, which is involved in tumor growth, invasion, differentiation, and metastasis, is activated in various human cancers. However, the relationship of autophagy and VHL in tumor progression remains controversial. Here, we showed that the expression levels of VHL and microtubule-associated protein 1 light chain 3B (MAP1LC3B, LC3B) were inversely correlated with various tumor grades of RCC tissues. pVHL was found to possess the LIR motif within a beta domain that interacted with MAP1LC3B and ubiquitinated it. The L101A VHL mutant failed to interact with MAP1LC3B, thereby failing to induce ubiquitination. MAP1LC3B-mediated autophagy was inhibited by functional pVHL and the ubiquitination of MAPLC3B was implicated in autophagy-induced cell death. We screened various autophagy inducers to determine the physiological function of the inhibition of LC3B-mediated autophagy by pVHL using VHL-deficient and VHL-expressing cell lines. MLN9708, a proteasome inhibitor, potently induced autophagy via the induction of MAP1LC3B and sensitized the cell to autophagy-mediated cell death in VHL-deficient and VHL-mutant (L101A) cells. In conclusion, our results showed that pVHL interacts with MAPL1LC3B and inhibits LC3B-mediated autophagy via MAP1LC3B ubiquitination. Furthermore, the activation of autophagy by the proteasome inhibitor MLN9708 induced cell death, indicating that MLN9708 can be used for VHL-deficient RCC therapy.

中文翻译：

pVHL对MAP1LC3B的泛素化作用与肾细胞癌的自噬和细胞死亡有关。

在高级RCC中，Von Hippel Lindau（VHL）的表达显着降低，并且在多种人类癌症中激活了与肿瘤生长，侵袭，分化和转移有关的自噬。然而，自噬与VHL在肿瘤进展中的关系仍存在争议。在这里，我们表明VHL和微管相关蛋白1轻链3B（MAP1LC3B，LC3B）的表达水平与RCC组织的各种肿瘤等级呈负相关。发现pVHL在与MAP1LC3B相互作用并泛素化的β域内具有LIR基序。L101A VHL突变体无法与MAP1LC3B相互作用，从而无法诱导泛素化。MAP1LC3B介导的自噬被功能性pVHL抑制，而MAPLC3B的泛素化与自噬诱导的细胞死亡有关。我们筛选了各种自噬诱导剂，以确定使用VHL缺失和表达VHL的pVHL抑制LC3B介导的自噬的生理功能。蛋白酶体抑制剂MLN9708通过MAP1LC3B的诱导有效诱导自噬，并使细胞对VHL缺失和VHL突变（L101A）细胞中自噬介导的细胞死亡敏感。总之，我们的结果表明pVHL与MAPL1LC3B相互作用并通过MAP1LC3B泛素化抑制LC3B介导的自噬。此外，蛋白酶体抑制剂MLN9708对自噬的激活引起细胞死亡，这表明MLN9708可用于VHL缺陷型RCC治疗。蛋白酶体抑制剂，通过MAP1LC3B的诱导有效诱导自噬，并使细胞对VHL缺失和VHL突变（L101A）细胞中自噬介导的细胞死亡敏感。总之，我们的结果表明pVHL与MAPL1LC3B相互作用并通过MAP1LC3B泛素化抑制LC3B介导的自噬。此外，蛋白酶体抑制剂MLN9708对自噬的激活引起细胞死亡，这表明MLN9708可用于VHL缺陷型RCC治疗。蛋白酶体抑制剂，通过MAP1LC3B的诱导有效诱导自噬，并使细胞对VHL缺失和VHL突变（L101A）细胞中自噬介导的细胞死亡敏感。总之，我们的结果表明pVHL与MAPL1LC3B相互作用并通过MAP1LC3B泛素化抑制LC3B介导的自噬。此外，蛋白酶体抑制剂MLN9708对自噬的激活引起细胞死亡，这表明MLN9708可用于VHL缺陷型RCC治疗。

更新日期：2019-03-22

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