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4E-BP, the key to lymphocyte sensitivity
In most cells, the mammalian (mechanistic) target of rapamycin complex 1 (mTORC1) regulates cell growth through the ribosomal S6 kinases (S6Ks) and cell proliferation through translation-regulating proteins of the eIF4E-binding protein (4E-BP) family, respectively. Although mTORC1 is present in all cells, the mTORC1 inhibitor rapamycin is an effective immunosuppressant that blocks lymphocyte proliferation (see the Focus by Abraham). But, why are lymphocytes so exquisitely sensitive? So et al. found that lymphocytes did not depend on S6K signaling to promote growth or proliferation in response to antigen receptor stimulation. Instead, these cells relied on 4E-BP proteins for both processes. Unlike in nonlymphoid cells, the 4E-BP2 isoform was more abundant than the 4E-BP1 isoform in lymphocytes, and its phosphorylation by mTORC1 was more sensitive to rapamycin. These data suggest that the exquisite sensitivity of lymphocytes to rapamycin may be due to their complete reliance on 4E-BP2 for both growth and proliferation.
Rapamycin has been used as a clinical immunosuppressant for many years; however, the molecular basis for its selective effects on lymphocytes remains unclear. We investigated the role of two canonical effectors of the mammalian target of rapamycin (mTOR): ribosomal S6 kinases (S6Ks) and eukaryotic initiation factor 4E (eIF4E)–binding proteins (4E-BPs). S6Ks are thought to regulate cell growth (increase in cell size), and 4E-BPs are thought to control proliferation (increase in cell number), with mTORC1 signaling serving to integrate these processes. However, we found that the 4E-BP–eIF4E signaling axis controlled both the growth and proliferation of lymphocytes, processes for which the S6Ks were dispensable. Furthermore, rapamycin disrupted eIF4E function selectively in lymphocytes, which was due to the increased abundance of 4E-BP2 relative to that of 4E-BP1 in these cells and the greater sensitivity of 4E-BP2 to rapamycin. Together, our findings suggest that the 4E-BP–eIF4E axis is uniquely rapamycin-sensitive in lymphocytes and that this axis promotes clonal expansion of these cells by coordinating growth and proliferation.