The protein lysine methyltransferase, SMYD2 is involved in diverse cellular events by regulating protein functions through lysine methylation. Though several substrate proteins of SMYD2 are well-studied, only a limited number of its interaction partners have been identified and characterized. Here, we performed a yeast two-hybrid screening of SMYD2 and found that the ribosomal protein, eL21 could interact with SMYD2. SMYD2-eL21 interaction in the human cells was confirmed by immunoprecipitation methods. In vitro pull-down assays revealed that SMYD2 interacts with eL21 directly through its SET and MYND domain. Computational mapping, followed by experimental studies identified that Lys81 and Lys83 residues of eL21 are important for the SMYD2-eL21 interaction. Evolutionary analysis showed that these residues might have co-evolved with the emergence of SMYD2. We found that eL21 regulates the steady state levels of SMYD2 by promoting its transcription and inhibiting its proteasomal degradation. Importantly, SMYD2-eL21 interaction plays an important role in regulating cell proliferation and its dysregulation might lead to tumorigenesis. Our findings highlight a novel extra-ribosomal function of eL21 on regulating SMYD2 levels and imply that ribosomal proteins might regulate wide range of cellular functions through protein-protein interactions in addition to their core function in translation.

蛋白质赖氨酸甲基转移酶 SMYD2 通过赖氨酸甲基化调节蛋白质功能参与多种细胞事件。尽管对 SMYD2 的几种底物蛋白进行了充分研究，但仅鉴定和表征了有限数量的其相互作用伙伴。在这里，我们对 SMYD2 进行了酵母双杂交筛选，发现核糖体蛋白 eL21 可以与 SMYD2 相互作用。通过免疫沉淀方法证实了 SMYD2-eL21 在人细胞中的相互作用。体外下拉分析显示 SMYD2 直接通过其 SET 和 MYND 结构域与 eL21 相互作用。计算映射，随后的实验研究确定 eL21 的 Lys81 和 Lys83 残基对 SMYD2-eL21 相互作用很重要。进化分析表明，这些残基可能与 SMYD2 的出现共同进化。我们发现 eL21 通过促进 SMYD2 的转录和抑制其蛋白酶体降解来调节 SMYD2 的稳态水平。重要的是，SMYD2-eL21 相互作用在调节细胞增殖中起重要作用，其失调可能导致肿瘤发生。