The HIV-1 nuclear export complex reveals the role of RNA in CRM1 cargo recognition

HIV utilizes host proteins to manipulate cellular processes during replication. One key interaction involves the HIV regulatory protein Rev with the highly conserved nuclear exportin chromosome region maintenance 1(CRM1), which exports >1,000 proteins and ribonucleoprotein (RNP) complexes from the nucleus to the cytoplasm. Rev, with its associated viral RNA, is the first identified RNP cargo of CRM1. Here, we present the cryogenic-electron microscopy (cryo-EM) structure of the HIV-1 Rev/Rev response element (RRE)/CRM1/Ran nuclear export complex. A Rev dimer engages a unique CRM1 dimer at an uncharacterized cargo-binding site at the core of the complex, positioning the RRE within a charged pocket inside one CRM1 subunit. Direct contacts between the RNA and CRM1/Ran-guanosine triphosphate (GTP) highlight the critical role of the RRE. The structure, together with guided mutations and cellular assays, provides not only an unprecedented view of HIV RNA transport but also illuminates how CRM1 can recognize a diverse range of protein and RNP cargos.