Siah-1 facilitates ubiquitination and degradation of factor inhibiting HIF-1alpha (FIH).
Hypoxia-inducible factor-1alpha (HIF-1alpha) has a central role in neuroprotective responses to hypoxia in the brain. Hydroxylation of HIF-1alpha by prolyl-hydroxylase PHD and aspargynyl-hydroxylase FIH (factor inhibiting HIF-1alpha) causes proteasomal degradation and transcriptional inhibition of HIF-1alpha. Siah ubiquitin ligases regulate the abundance of PHD via targeting for proteasomal degradation. The present study identified Siah-1 as a binding partner for another hydroxylase FIH. Siah-1 and FIH coimmunoprecipitated each other in mammalian cells. Siah-1 was found both to interact with the JmjC domain of FIH through its substrate-binding domain and to specifically ubiquitinate FIH via its RING finger domain. Siah-1 facilitated FIH degradation via the ubiquitin-proteasome pathway under hypoxic conditions. Such findings suggest that Siah ubiquitin ligases might play a role as up-stream regulators of both hydroxylases for HIF-1alpha, i.e., PHD and FIH, by targeting them for proteasomal degradation, leading to increased HIF-1alpha abundance, and transcriptional activity in hypoxia.
Fukuba
Hiromasa
H
Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical Sciences, 1-2-3 Kasumi, Hiroshima 734-8551, Japan.
Yamashita
Hiroshi
H
Nagano
Yoshito
Y
Jin
Hong Guo
HG
Hiji
Masanori
M
Ohtsuki
Toshiho
T
Takahashi
Tetsuya
T
Kohriyama
Tatsuo
T
Matsumoto
Masayasu
M
D015687:Cell Hypoxia / Q000502:physiology; D002460:Cell Line; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D006899:Mixed Function Oxygenases; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000098563:Seven in Absentia Proteins
D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D046988:Proteasome Endopeptidase Complex