Ubiquitination of CD98 limits cell proliferation and clonal expansion

Abstract

CD98 facilitates lymphocyte clonal expansion that enables adaptive immunity; conversely, increased expression of CD98 is a feature of both lymphomas and leukemias and represents a potential therapeutic target in these diseases. CD98 is transcriptionally regulated and ectopic expression of certain Membrane Associated RING-CH(MARCH) E3 ubiquitin ligases, MARCH1 or MARCH8, leads to ubiquitination and lysosomal degradation of CD98. Here we examined the potential role of ubiquitination in regulating CD98 expression and cell proliferation. We report that blocking ubiquitination by use of a catalytically-inactive MARCH or by creating a ubiquitination-resistant CD98 mutant , prevents MARCH-induced CD98 down-regulation in HeLa cells. MARCH1-null T cells display increased CD98 expression. Similarly, T cells expressing ubiquitination-resistant CD98 manifest increased proliferation in vitro and clonal expansion in vivo. Thus, ubiquitination and resulting downregulation of CD98 can limit cell proliferation and clonal expansion.