Ubiquitylation of CD98 limits cell proliferation and clonal expansion.
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.
Department of Medicine, University of California San Diego, La Jolla, CA 92093-0726, USA.
Jailal N G
JN
Ablack
Department of Medicine, University of California San Diego, La Jolla, CA 92093-0726, USA.
Patrick J
PJ
Metz
Department of Medicine, University of California San Diego, La Jolla, CA 92093-0726, USA.
John T
JT
Chang
Department of Medicine, University of California San Diego, La Jolla, CA 92093-0726, USA jmcantor@ucsd.edu mhginsberg@ucsd.edu.
Joseph M
JM
Cantor
Department of Medicine, University of California San Diego, La Jolla, CA 92093-0726, USA jmcantor@ucsd.edu mhginsberg@ucsd.edu.
Mark H
MH
Ginsberg
D000818:Animals; D049109:Cell Proliferation / Q000502:physiology*; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology*
D027282:Fusion Regulatory Protein 1, Heavy Chain; C545989:SLC3A2 protein, human; C523212:Slc3A2 protein, mouse; C545340:MARCH1 protein, mouse; C528121:MARCHF1 protein, human; C568898:MARCHF8 protein, human; C559132:March8 protein, mouse; D044767:Ubiquitin-Protein Ligases
CD98; Clonal expansion; Immunobiology; Integrin signaling