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Thalidomide and its metabolite 5‐hydroxythalidomide induce teratogenicity via the cereblon neosubstrate PLZF
Author(s) -
Yamanaka Satoshi,
Murai Hidetaka,
Saito Daisuke,
Abe Gembu,
Tokunaga Etsuko,
Iwasaki Takahiro,
Takahashi Hirotaka,
Takeda Hiroyuki,
Suzuki Takayuki,
Shibata Norio,
Tamura Koji,
Sawasaki Tatsuya
Publication year - 2021
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020105375
Subject(s) - cereblon , thalidomide , ubiquitin ligase , biology , zinc finger , ubiquitin , ubiquitin protein ligases , protein degradation , microbiology and biotechnology , cancer research , pharmacology , biochemistry , transcription factor , immunology , multiple myeloma , gene
Thalidomide causes teratogenic effects by inducing protein degradation via cereblon (CRBN)‐containing ubiquitin ligase and modification of its substrate specificity. Human P450 cytochromes convert thalidomide into two monohydroxylated metabolites that are considered to contribute to thalidomide effects, through mechanisms that remain unclear. Here, we report that promyelocytic leukaemia zinc finger (PLZF)/ZBTB16 is a CRBN target protein whose degradation is involved in thalidomide‐ and 5‐hydroxythalidomide‐induced teratogenicity. Using a human transcription factor protein array produced in a wheat cell‐free protein synthesis system, PLZF was identified as a thalidomide‐dependent CRBN substrate. PLZF is degraded by the ubiquitin ligase CRL4 CRBN in complex with thalidomide, its derivatives or 5‐hydroxythalidomide in a manner dependent on the conserved first and third zinc finger domains of PLZF. Surprisingly, thalidomide and 5‐hydroxythalidomide confer distinctly different substrate specificities to mouse and chicken CRBN, and both compounds cause teratogenic phenotypes in chicken embryos. Consistently, knockdown of Plzf induces short bone formation in chicken limbs. Most importantly, degradation of PLZF protein, but not of the known thalidomide‐dependent CRBN substrate SALL4, was induced by thalidomide or 5‐hydroxythalidomide treatment in chicken embryos. Furthermore, PLZF overexpression partially rescued the thalidomide‐induced phenotypes. Our findings implicate PLZF as an important thalidomide‐induced CRBN neosubstrate involved in thalidomide teratogenicity.