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KMID : 0578320200430110935
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Molecules and Cells
2020 Volume.43 No. 11 p.935 ~ p.944
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Aryl Sulfonamides Induce Degradation of Aryl Hydrocarbon Receptor Nuclear Translocator through CRL4DCAF15 E3 Ligase
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Kim Sung-Ah
Jo Seung-Hyun
Cho Jin-Hwa
Yu Min-Yeong
Shin Ho-Chul
Kim Jung-Ae
Park Sung-Goo
Park Byoung-Chul
Kim Sun-Hong
Kim Jeong-Hoon
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Abstract
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Aryl hydrocarbon receptor nuclear translocator (ARNT) plays an essential role in maintaining cellular homeostasis in response to environmental stress. Under conditions of hypoxia or xenobiotic exposure, ARNT regulates the subset of genes involved in adaptive responses, by forming heterodimers with hypoxia-inducible transcription factors (HIF1α and HIF2α) or aryl hydrocarbon receptor (AhR). Here, we have shown that ARNT interacts with DDB1 and CUL4-associated factor 15 (DCAF15), and the aryl sulfonamides, indisulam and E7820, induce its proteasomal degradation through Cullin-RING finger ligase 4 containing DCAF15 (CRL4DCAF15) E3 ligase. Moreover, the two known neo-substrates of aryl sulfonamide, RNA-binding motif protein 39 (RBM39) and RNA-binding motif protein 23 (RBM23), are not required for ARNT degradation. In line with this finding, aryl sulfonamides inhibited the transcriptional activities of HIFs and AhR associated with ARNT. Our results collectively support novel regulatory roles of aryl sulfonamides in both hypoxic and xenobiotic responses.
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KEYWORD
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hydrocarbon receptor nuclear translocator, aryl sulfonamide, cullin ring ubiquitin ligase, DDB1 and CUL4 associated factor 15, E7820, indisulam
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