SIRT3 is a major mitochondrial deacetylase, which regulates various metabolic pathways by deacetylation; however, the effect of SIRT3 on proline metabolism is not reported. Pyrroline-5-carboxylate reductase 1 (PYCR1) participates in proline synthesis process by catalyzing the reduction of P5C to proline with concomitant generation of NAD+ and NADP+. PYCR1 is highly expressed in various cancers, and it can promote the growth of tumor cells. Here, through immunoprecipitation and mass spectrometry, we found that PYCR1 is in SIRT3's interacting network. PYCR1 directly binds to SIRT3 both in vivo and in vitro. CBP is the acetyltransferase for PYCR1, whereas SIRT3 deacetylates PYCR1. We further identified that K228 is the major acetylation site for PYCR1. Acetylation of PYCR1 at K228 reduced its enzymatic activity by impairing the formation of the decamer of PYCR1. As a result, acetylation of PYCR1 at K228 inhibits cell proliferation, while deacetylation of PYCR1 mediated by SIRT3 increases PYCR1's activity. Our findings on the regulation of PYCR1 linked proline metabolism with SIRT3, CBP and cell growth, thus providing a potential approach for cancer therapy.

中文翻译：

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SIRT3 通过脯氨酸代谢中 PYCR1 的去乙酰化来调节癌细胞增殖。


SIRT3是一种主要的线粒体脱乙酰酶，通过脱乙酰作用调节多种代谢途径；然而，SIRT3对脯氨酸代谢的影响尚未见报道。吡咯啉-5-羧酸还原酶 1 (PYCR1) 通过催化 P5C 还原为脯氨酸并同时生成 NAD+ 和 NADP+ 来参与脯氨酸合成过程。 PYCR1在多种癌症中高表达，能够促进肿瘤细胞的生长。在这里，通过免疫沉淀和质谱分析，我们发现PYCR1位于SIRT3的相互作用网络中。 PYCR1 在体内和体外均直接与 SIRT3 结合。 CBP 是 PYCR1 的乙酰转移酶，而 SIRT3 使 PYCR1 去乙酰化。我们进一步确定 K228 是 PYCR1 的主要乙酰化位点。 PYCR1 在 K228 处的乙酰化通过损害 PYCR1 十聚体的形成来降低其酶活性。因此，PYCR1 在 K228 处的乙酰化会抑制细胞增殖，而 SIRT3 介导的 PYCR1 去乙酰化会增加 PYCR1 的活性。我们对 PYCR1 调节的发现将脯氨酸代谢与 SIRT3、CBP 和细胞生长联系起来，从而为癌症治疗提供了一种潜在的方法。