Tetraspanins CD9 and CD81 function to prevent the fusion of mononuclear phagocytes

Abstract

Tetraspanins CD9 and CD81 facilitate the fusion between gametes, myoblasts, or virus-infected cells. Here, we investigated the role of these tetraspanins in the fusion of mononuclear phagocytes. Expression of CD9 and CD81 and their complex formation with integrins were up-regulated when blood monocytes were cultured under normal conditions. Under fusogenic conditions in the presence of Con A, CD9 and CD81 up-regulation was inhibited, and their complex formation with integrins was down-regulated. Anti-CD9 and -CD81 antibodies, which were previously shown to inhibit the fusion of gametes, myoblasts, and virus-infected cells, unexpectedly promoted the fusion of monocytes and alveolar macrophages. However, these effects were not due to altered cell adhesion, aggregation, or cytokine production. When stimulated in vitro or in vivo, alveolar macrophages and bone marrow cells of CD9- and CD81-null mice formed larger numbers of multinucleated cells than those of wild-type mice. Finally, CD9/CD81 double-null mice spontaneously developed multinucleated giant cells in the lung and showed enhanced osteoclastogenesis in the bone. These results suggest that CD9 and CD81 coordinately prevent the fusion of mononuclear phagocytes.

Normal muscle regeneration requires tight control of muscle cell fusion by tetraspanins CD9 and CD81

“…In addition, in the absence of either CD9 or CD81 alveolar macrophages had an increased ability to form multinuclear giant cells both in vitro and in vivo, in response to Propionibacterium acnes. However, mice spontaneously developed multinuclear giant cells in the lung only in the absence of both tetraspanins 15 . The similar roles of CD9 and CD81 in several fusion processes are probably linked to their relatively high degree of identity as compared with other tetraspanins, and to their ability to directly associate with the same partner proteins, including CD9P-1 and EWI-2, another protein of unknown function related to CD9P-1 (refs 19-22).…”

“…CD81 À / À mice are hypofertile and CD9 À / À ::CD81 À / À mice are completely infertile, suggesting a cooperative role of CD9 and CD81 in sperm/egg fusion 13 . However, both CD9 and CD81 negatively regulate HIV-induced cell fusion 14 and macrophage fusion 15 . Altogether, these studies indicate that CD9 and CD81 can act both as positive and negative regulators of cell-cell fusion processes.…”

Osteoclast stimulatory transmembrane protein and dendritic cell–specific transmembrane protein cooperatively modulate cell–cell fusion to form osteoclasts and foreign body giant cells

“…(13) Therefore, although the functions of osteoclasts and FBGCs differ, they express common molecules, such as DC-STAMP, that function in cell-cell fusion. (3) To date, various molecules have been identified that regulate fusion of osteoclasts or macrophages, including DC-STAMP, ATP6v0d2, CD47, CD44, CD9, CD81, MFR, E-cadherin, and meltrin-a (3,(14)(15)(16)(17)(18)(19)(20)(21) ATP6v0d2-deficient mice show significant reductions in fusion of either cell type. (21) DC-STAMP-deficient osteoclasts or FBGCs show a complete lack of cell-cell fusion, a function specific for macrophage lineage fusion, since fertilization and myotube formation is normal in DC-STAMP-deficient mice.…”

Cell fusion promotes chemoresistance in metastatic colon carcinoma

“…In particular, tetraspanin CD9 and CD81 have been implicated in muscle cell fusion, mononuclear phagocytes and linked to the virus-induced syncitium formation. [15][16][17] ADAMs were initially discovered as proteins involved in fertilization, muscle fusion and organ development. 18,19 In this study, we provide evidence that proteins ADAM10, GTP-binding protein a13, radixin, myosin regulatory light chain and RhoA promote cell fusion in colon cancer cells.…”