小柯机器人

美国哈佛医学院Edward T. Chouchani研究组发现，乳酸通过重塑后期促进复合体来调节细胞周期。这一研究成果于2023年3月15日在线发表在国际学术期刊《自然》上。

研究人员设计了一个系统的方法来确定乳酸依赖性的蛋白质在整个人类蛋白质组中的调节。从这些数据中，研究人员阐明了一种细胞周期调节机制，即累积的乳酸会重塑促进后期促进复合体（APC/C）。以这种方式重塑APC/C是由乳酸直接抑制SUMO蛋白酶SENP1造成的。研究人员发现，累积的乳酸与SENP1活性部位的锌形成复合物，从而结合并抑制SENP1。乳酸对SENP1的抑制稳定了APC4上两个残基的SUMO化，从而促使UBE2C与APC结合。乳酸对APC/C的这种直接调节刺激了细胞周期蛋白的定时降解，以及增殖期人类细胞的有效有丝分裂退出。上述机制是在有丝分裂进入时启动的，当时乳酸的丰度达到顶点。这样，乳酸的积累传达了营养丰富的生长阶段的后果，从而刺激APC/C的适时开放、细胞分裂和增殖。相反，乳酸的持续积累促使APC/C的异常重塑，并能通过有丝分裂降低克服抗有丝分裂的药理。

综上所述，研究人员定义了一种生化机制，通过该机制，乳酸直接调节蛋白质功能，控制细胞周期和增殖。

研究人员表示，由于需要提高葡萄糖分解率来支持增殖，乳酸在快速分裂的细胞中很丰富。然而，目前还不知道累积的乳酸是否会影响增殖的状态。

附：英文原文

Title: Lactate regulates cell cycle by remodeling the anaphase promoting complex

Author: Liu, Weihai, Wang, Yun, Bozi, Luiz H. M., Fischer, Patrick, Jedrychowski, Mark P., Xiao, Haopeng, Wu, Tao, Darabedian, Narek, He, Xiadi, Mills, Evanna L., Burger, Nils, Shin, Sanghee, Reddy, Anita, Sprenger, Hans-Georg, Tran, Nhien, Winther, Sally, Hinshaw, Stephen M., Shen, Jingnan, Seo, Hyuk-Soo, Song, Kijun, Xu, Andrew Z., Sebastian, Luke, Zhao, Jean, Dhe-Paganon, Sirano, Che, Jianwei, Gygi, Steven P., Arthanari, Haribabu, Chouchani, Edward T.

Issue&Volume: 2023-03-15

Abstract: Lactate is abundant in rapidly dividing cells due to the requirement for elevated glucose catabolism to support proliferation1-6. However, it is not known whether accumulated lactate affects the proliferative state. Here, we deploy a systematic approach to determine lactate-dependent regulation of proteins across the human proteome. From these data, we elucidate a mechanism of cell cycle regulation whereby accumulated lactate remodels the anaphase promoting complex (APC/C). Remodeling of APC/C in this way is caused by direct inhibition of the SUMO protease SENP1 by lactate. We discover that accumulated lactate binds and inhibits SENP1 by forming a complex with zinc in the SENP1 active site. SENP1 inhibition by lactate stabilizes SUMOylation of two residues on APC4, which drives UBE2C binding to APC/C. This direct regulation of APC/C by lactate stimulates timed degradation of cell cycle proteins, and efficient mitotic exit in proliferative human cells. The above mechanism is initiated upon mitotic entry when lactate abundance reaches its apex. In this way, accumulation of lactate communicates the consequences of a nutrient replete growth phase to stimulate timed opening of APC/C, cell division, and proliferation. Conversely, persistent accumulation of lactate drives aberrant APC/C remodeling and can overcome anti-mitotic pharmacology via mitotic slippage. Taken together, we define a biochemical mechanism through which lactate directly regulates protein function to control cell cycle and proliferation.

DOI: 10.1038/s41586-023-05939-3

Source: https://www.nature.com/articles/s41586-023-05939-3

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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