In This Issue . . .

STAT3 is pivotal for a wide variety of immune responses. Dimerization, phosphorylation at specific residues and shuttling between cellular compartments are crucial for STAT3 functions. Phosphorylation at Tyr705 (pY705) allows interaction with the SH2 domain of a partner STAT3 molecule and thus stabilizes dimerization. Phosphorylation of Ser727 (pS727) affects the activity of STAT3 but the detailed structural and biological mechanisms are not established. Here, Yang et al. show that pS727, in cooperation with N-terminal domain (NTD) ‘hand-shake’ dimerization, accelerates the STAT3 activation–inactivation cycle, leading to pY705 de-phosphorylation and CRM1-independent post-activation export from the nucleus. Inhibition of STAT3 activation–inactivation cycles delays responses to IL-6. Interactions of the C-terminal tail (CTT) with SH2 on the same molecule and CTT on the partner STAT3 molecule support pY705–SH2 association and sustain pY705 activation; pS727 weakens these interactions by phosphorylation or acetylation of the CTT to inactivate STAT3. The authors thus construct a multi-step model of pS727-regulated STAT3 inactivation.