Abstract：
SLC7A11 is a cystine transporter and ferroptosis inhibitor. How the stability of SLC7A11 is coordinately regulated in response to environmental cystine by which E3 ligase and deubiquitylase (DUB) remains elusive. Here, we report that neddylation inhibitor MLN4924 increases cystine uptake by causing SLC7A11 accumulation, via inactivating Cullin-RING ligase-3 (CRL-3). We identified KCTD10 as the substrate-recognizing subunit of CRL-3 for SLC7A11 ubiquitylation, and USP18 as SLC7A11 deubiquitylase. Upon cystine deprivation, the protein levels of KCTD10 or USP18 are decreased or increased, respectively, contributing to SLC7A11 accumulation. By destabilizing or stabilizing SLC7A11, KCTD10, or USP18 inversely regulates the cystine uptake and ferroptosis. Biologically, MLN4924 combination with SLC7A11 inhibitor Imidazole Ketone Erastin (IKE) enhanced suppression of tumor growth. In human breast tumor tissues, SLC7A11 levels were negatively or positively correlated with KCTD10 or USP18, respectively. Collectively, our study defines how SLC7A11 and ferroptosis is coordinately regulated by the CRL3KCTD10/E3-USP18/DUB axis, and provides a sound rationale of drug combination to enhance anticancer efficacy.
摘要：
SLC7A11是胱氨酸转运蛋白和铁凋亡抑制剂。SLC7A11的稳定性如何在响应环境胱氨酸时协调调节，E3连接酶和去泛素酶（DUB）仍然难以捉摸。这里,我们报道neddylation抑制剂MLN4924通过引起SLC7A11积累来增加胱氨酸的摄取，通过灭活Cullin-RING连接酶-3（CRL-3）。我们将KCTD10鉴定为CRL-3用于SLC7A11泛素化的底物识别亚基，和USP18作为SLC7A11去泛素酶。剥夺胱氨酸后，KCTD10或USP18的蛋白质水平降低或升高，分别,有助于SLC7A11的积累。通过使SLC7A11、KCTD10或USP18不稳定或稳定,反向调节胱氨酸摄取和铁凋亡。生物学,MLN4924与SLC7A11抑制剂咪唑酮伊拉斯汀（IKE）的组合增强了对肿瘤生长的抑制。在人类乳腺肿瘤组织中，SLC7A11水平分别与KCTD10或USP18呈负相关或正相关。总的来说，我们的研究定义了SLC7A11和铁凋亡如何由CRL3KCTD10/E3-USP18/DUB轴协调调节，并提供了合理的药物组合以增强抗癌功效的基本原理。
