Association of CD147 and Calcium Exporter PMCA4 Uncouples IL-2 Expression from Early TCR Signaling

Abstract

The Ig superfamily member CD147 is upregulated following T cell activation and was shown to serve as a negative regulator of T cell proliferation. Thus, Abs targeting CD147 are being tested as new treatment strategies for cancer and autoimmune diseases. How CD147 mediates immunosuppression and whether association with other coreceptor complexes is needed have remained unknown. In the current study, we show that silencing of CD147 in human T cells increases IL-2 production without affecting the TCR proximal signaling components. We mapped the immunosuppressive moieties of CD147 to its transmembrane domain and Ig-like domain II. Using affinity purification combined with mass spectrometry, we determined the domain specificity of CD147 interaction partners and identified the calcium exporter plasma membrane calcium ATPase isoform 4 (PMCA4) as the interaction partner of the immunosuppressive moieties of CD147. CD147 does not control the proper membrane localization of PMCA4, but PMCA4 is essential for the CD147-dependent inhibition of IL-2 expression via a calcium-independent mechanism. In summary, our data show that CD147 interacts via its immunomodulatory domains with PMCA4 to bypass TCR proximal signaling and inhibit IL-2 expression

CD147 promotes progression of head and neck squamous cell carcinoma via NF‐kappa B signaling

“…As our previous study shown, CD147 is considered to be a HNSCC cell surface marker that could enhance the tumor initiation and progression . Studies also demonstrated that CD147 had negative role in regulating in T cell‐mediated immune responses and drugs targeting CD147 had anti‐angiogenesis and anti‐invasion activity . Our data determined that CD147 exerted positive effect on tumorigenicity and cancer progression of HNSCC both in vitro and in vivo.…”

“…5 Studies also demonstrated that CD147 had negative role in regulating in T cell-mediated immune responses and drugs targeting CD147 had anti-angiogenesis and anti-invasion activity. [25][26][27][28] Our data determined that CD147 exerted positive effect on tumorigenicity and cancer progression of HNSCC both in vitro and in vivo. In addition, CD147 expression level is positively correlated with clinical outcome and tumor histological grade in HNSCC.…”

Dynamic Interaction- and Phospho-Proteomics Reveal Lck as a Major Signaling Hub of CD147 in T Cells

“…Further, two studies have reported reduced phosphorylation of early TCR signaling components and reduced calcium mobilization upon CD147 silencing (34) or CD147 Ab treatment (7), whereas in another study enhanced JNK and p21-activated kinase 1 activation and thus higher NFAT transcriptional activity in CD147-silenced cells has been reported (48). We showed recently that interaction of CD147 with the plasma membrane calcium ATPase isoform 4 (PMCA4) bypasses TCR proximal signaling and inhibits IL-2 expression (64). Nevertheless, the understanding of the molecular functionality of CD147 is still incomplete.…”

“…The lentiviral packaging plasmids psPAX and pMD2.G were from Addgene (Cambridge, MA); the pLKO.1-puro-nonmammalian short hairpin RNA (shRNA) control (shControl) was supplied by the German Science Center for Genome Research (Berlin, Germany). The pLKO.1-puro-CD147_333 (shCD147) containing an shRNA construct specific for human CD147 and the pBMN-IRES-GFP-HACD147etc containing the RNA interference (RNAi)resistant full-length CD147 with a hemagglutinin (HA)-tag (HACD147etc) were cloned as described previously (64).…”

“…To examine how the microenvironment of CD147 changes during T cell stimulation, we employed AP-MS in the presence or absence of T cell stimulating agents. We retrovirally transferred HACD147etc as we described earlier (64) into CD147-silenced Jurkat T cells. Then we treated the cells with T cell stimulating agents for the indicated time points.…”