Key Points MARCH E3 ubiquitin ligases regulate responses to anti-tumor Abs. The tumor’s MARCH protein repertoire may determine sensitivity to those Abs. CD98, which is required for the rapid proliferation of both normal and cancer cells, and MET, the hepatocyte growth factor receptor, are potential targets for therapeutic antitumor Abs. In this study, we report that the antiproliferative activity of a prototype anti-CD98 Ab, UM7F8, is due to Ab-induced membrane-associated ring CH (MARCH) E3 ubiquitin ligase-mediated ubiquitination and downregulation of cell surface CD98. MARCH1-mediated ubiquitination of CD98 is required for UM7F8’s capacity to reduce CD98 surface expression and its capacity to inhibit the proliferation of murine T cells. Similarly, CD98 ubiquitination is required for UM7F8’s capacity to block the colony-forming ability of murine leukemia–initiating cells. To test the potential generality of the paradigm that MARCH E3 ligases can mediate the antiproliferative response to antitumor Abs, we examined the potential effects of MARCH proteins on responses to emibetuzumab, an anti-MET Ab currently in clinical trials for various cancers. We report that MET surface expression is reduced by MARCH1, 4, or 8-mediated ubiquitination and that emibetuzumab-induced MET ubiquitination contributes to its capacity to downregulate MET and inhibit human tumor cell proliferation. Thus, MARCH E3 ligases can act as cofactors for antitumor Abs that target cell surface proteins, suggesting that the MARCH protein repertoire of cells is a determinant of their response to such Abs.

中文翻译：

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MARCH 蛋白介导对抗肿瘤抗体的反应

关键点 MARCH E3 泛素连接酶调节对抗肿瘤抗体的反应。肿瘤的 MARCH 蛋白库可能决定对这些 Abs 的敏感性。CD98 是正常细胞和癌细胞快速增殖所必需的，而 MET 是肝细胞生长因子受体，是治疗性抗肿瘤抗体的潜在靶点。在这项研究中，我们报告了原型抗 CD98 抗体 UM7F8 的抗增殖活性是由于 Ab 诱导的膜相关环 CH (MARCH) E3 泛素连接酶介导的泛素化和细胞表面 CD98 的下调。MARCH1 介导的 CD98 泛素化是 UM7F8 降低 CD98 表面表达的能力及其抑制鼠 T 细胞增殖的能力所必需的。相似地，CD98 泛素化是 UM7F8 阻断小鼠白血病起始细胞集落形成能力所必需的。为了测试 MARCH E3 连接酶可以介导对抗肿瘤 Abs 的抗增殖反应的范式的潜在普遍性，我们检查了 MARCH 蛋白对 emibetuzumab 反应的潜在影响，emibetuzumab 是一种目前在各种癌症的临床试验中的抗 MET Ab。我们报告 MET 表面表达因 MARCH1、4 或 8 介导的泛素化而降低，并且 emibetuzumab 诱导的 MET 泛素化有助于其下调 MET 和抑制人类肿瘤细胞增殖的能力。因此，MARCH E3 连接酶可以作为靶向细胞表面蛋白的抗肿瘤 Abs 的辅助因子，这表明细胞的 MARCH 蛋白库是它们对此类 Abs 反应的决定因素。