Secretory Leukocyte Protease Inhibitor Binds to Annexin II, a Cofactor for Macrophage HIV-1 Infection

Ma, Ge; Greenwell-Wild, Teresa; Lei, Kejian; Jin, Wenwen; Swisher, Jennifer; Hardegen, Neil; Wild, Carl T.; Wahl, Sharon M.

Despite tremendous efforts over the last decade, a cell surface receptor for SLPI has remained elusive. To decipher the mechanisms by which SLPI regulates target cell functions independent of protease inhibition, we searched for a membrane-binding protein/receptor for SLPI on mononuclear phagocytes that are susceptible to its antiinflammatory and antiviral activities (2) (3) (4) (6) (7) (8) . In this study, we document that SLPI binding to the macrophage cell membrane involves annexin II. Annexin II is a member of the larger annexin gene family and contains a variable NH 2 -terminal tail, a COOH-terminal region with heparin and plasminogen-binding sites, and the core domain, which includes binding sites for Ca 2 ϩ , phospholipids, and F-actin (15) (16) (17) (18) . Characterized by a highly conserved set of ␣ -helical repeats that mediate membrane binding, annexin II exists as a monomer (p36) or a heterotetramer constructed of two p36 and two p11(S100A10) subunits, and traffics to the cell surface by an unknown mechanism (18) . Although implicated in exocytosis and endocytosis pathways, as well as in ion channel activity and stimulation of DNA replication (17) , annexin II has not previously been linked to HIV-1. Nonetheless, annexin II has recently been identified as a receptor for CMV (19) and respiratory syncytial virus (20) , prompting our exploration of a potential role for annexin II in HIV-1 infection and as a conduit for inhibition by SLPI and/or other targeted interventions in the battle against AIDS.