Ubiquitylation of CD98 limits cell proliferation and clonal expansion
Ubiquitylation of CD98 limits cell proliferation and clonal expansion
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DOI：
10.1242/jcs.178129
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发表时间：
2015-12-01
影响因子：
4
通讯作者：
Ginsberg, Mark H.
中科院分区：
文献类型：
--
作者：
Ablack, Jailal N. G.;Metz, Patrick J.;Ginsberg, Mark H.
CD98重链（SLC3A2）促进淋巴细胞克隆扩增，实现适应性免疫；然而，CD98的表达增加也是淋巴瘤和白血病的一个特征，并代表了这些疾病的潜在治疗靶点。CD98受转录调控，膜相关环- ch (MARCH) E3泛素连接酶MARCH1或MARCH8的异位表达可导致CD98的泛素化和溶酶体降解。在这里，我们研究了泛素化在调节CD98表达和细胞增殖中的潜在作用。我们报道，通过使用无催化活性的MARCH或通过创建抗泛素化的CD98突变体来阻断泛素化，可以防止HeLa细胞中MARCH诱导的CD98下调。无march1的T细胞显示CD98表达增加。同样，表达抗泛素化CD98的T细胞在体外增殖和体内克隆扩增均增加。因此，泛素化和由此导致的CD98下调可以限制细胞增殖和克隆扩增。
CD98 heavy chain (SLC3A2) facilitates lymphocyte clonal expansion that enables adaptive immunity; however, increased expression of CD98 is also a feature of both lymphomas and leukemias and represents a potential therapeutic target in these diseases. CD98 is transcriptionally regulated and ectopic expression of the membrane-associated RING-CH (MARCH) E3 ubiquitin ligases MARCH1 or MARCH8 leads to ubiquitylation and lysosomal degradation of CD98. Here, we examined the potential role of ubiquitylation in regulating CD98 expression and cell proliferation. We report that blocking ubiquitylation by use of a catalytically inactive MARCH or by creating a ubiquitylation-resistant CD98 mutant, prevents MARCH-induced CD98 downregulation in HeLa cells. March1-null T cells display increased CD98 expression. Similarly, T cells expressing ubiquitylation-resistant CD98 manifest increased proliferation in vitro and clonal expansion in vivo. Thus, ubiquitylation and the resulting downregulation of CD98 can limit cell proliferation and clonal expansion.