In the 1950s the drug thalidomide administered as a sedative to pregnant women led to the birth of thousands of children with multiple defects. Despite its teratogenicity, thalidomide and its derivatives lenalidomide and pomalidomide (together known as Immunomodulatory Drugs: IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-dysplasia. IMiDs target the CUL4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase and promote the ubiquitination of Ikaros/Aiolos transcription factors by CRL4CRBN. Here we present the crystal structure of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes CRBN as a CRL4CRBN substrate receptor, which enantioselectively binds IMiDs. Through an unbiased screen we identify the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4CRBN. Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4CRBN when recruiting Ikaros/Aiolos for degradation. This dual activity implies that small molecules can principally modulate a ligase to up- or down-regulate the ubiquitination of proteins.

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At least five arenaviruses cause viral haemorrhagic fevers in humans. Lassa virus, an Old World arenavirus, uses the cellular receptor α-dystroglycan to infect cells 1 . Machupo, Guanarito, Junin and Sabia viruses are New World haemorrhagic fever viruses that do not use α-dystroglycan 2 . Here we show a specific, high-affinity association between transferrin receptor 1 (TfR1) and the entry glycoprotein (GP) of Machupo virus. Expression of human TfR1, but not human transferrin receptor 2, in hamster cell lines markedly enhanced the infection of viruses pseudotyped with the GP of Machupo, Guanarito and Junin viruses, but not with those of Lassa or lymphocytic choriomeningitis viruses. An anti-TfR1 antibody efficiently inhibited the replication of Machupo, Guanarito, Junin and Sabia viruses, but not that of Lassa virus. Iron depletion of culture medium enhanced, and iron supplementation decreased, the efficiency of infection by Junin and Machupo but not Lassa pseudoviruses. These data indicate that TfR1 is a cellular receptor for New World haemorrhagic fever arenaviruses.Arenaviruses are enveloped, single-stranded, bisegmented RNA viruses 3 . The family Arenaviridae consists of a single genus (Arenavirus), which includes at least 23 recognized viruses 4 . Arenaviruses have been classified into two antigenically and geographically distinct groups, the Lassa-lymphocytic choriomeningitis serocomplex ('Old World arenaviruses') and the Tacaribe serocomplex ('New World arenaviruses'). Five arenaviruses are known to cause acute viral haemorrhagic fever in humans, with case-fatality rates as high as 30%. Lassa virus (LASV) is an Old World arenavirus that causes Lassa fever.

Background: HUWE1 is an E3 ligase implicated in cancer and intellectual disabilities. Results: Inducible RNAi combined with quantitative diGly proteomics was implemented to find HUWE1 substrates. Conclusion: DDIT4 is a substrate of HUWE1. Significance: HUWE1 is a master regulator of cell stress response proteins including DDIT4. Inducible RNAi coupled with diGly proteomics is a valuable strategy for identifying novel E3 ligase substrates.