Research ArticleImmunology

The 4E-BP–eIF4E axis promotes rapamycin-sensitive growth and proliferation in lymphocytes

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Science Signaling  31 May 2016:
Vol. 9, Issue 430, pp. ra57
DOI: 10.1126/scisignal.aad8463

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.