MX2-mediated innate immunity against HIV-1 is regulated by serine phosphorylation

The antiviral cytokine interferon (IFN) activates expression of IFN-stimulated genes (ISGs) to establish an antiviral state. Myxovirus resistance 2 (MX2/MxB) is an ISG that inhibits the nuclear import of HIV-1 and interacts with the viral capsid and cellular nuclear transport machinery. We identified the myosin light chain phosphatase (MLCP) subunits MYPT1 and PPP1CB as positively-acting regulators of MX2, interacting with its N-terminal domain (NTD). We demonstrated that serine phosphorylation of the NTD at positions 14, 17 and 18 suppresses MX2 antiviral function, prevents interactions with the HIV-1 capsid and nuclear transport factors, and is reversed by MLCP. Importantly, NTD serine phosphorylation also impedes MX2-mediated inhibition of nuclear import of cellular karyophilic cargo. We additionally found that IFN treatment reduces levels of phosphorylation at these serines and outline a homeostatic regulatory mechanism where repression of MX2 by phosphorylation, together with MLCP-mediated dephosphorylation, balances the deleterious effects of MX2 upon normal cell function with innate immunity against HIV-1.