E3 ubiquitin ligases SIAH1/2 regulate hypoxia-inducible factor-1 (HIF-1)-mediated Th17 cell differentiation.
IL-17 is known to be a cytokine mainly secreted from Th17 cells, which well associate with autoimmune inflammatory responses. In the generation of Th17 cells, RORc and RORa have pivotal roles in controlling the transcription of Il17. We speculated additional regulation in Il17a transcription and randomly screened a 6344 clone cDNA library to identify specific modulators for Il17a promoter activity. After the screen, the E3 ubiquitin ligases SIAH1 and SIAH2 were investigated further and confirmed to increase Il17a promoter activity in a T-cell line and to promote Th17 development ex vivo. This enhancement was a consequence of enhanced expression of hypoxia-inducible factor-1α (HIF-1α) protein, which is reported to directly regulate expression of Il17a and Rorgt at the transcriptional level. In the absence of HIF-1α, both ubiquitin ligases had little effect on Th17 cell differentiation. These results suggest that the SIAH1 and SIAH2 play a pivotal role to promote Th17 cell differentiation through maintaining the stability of HIF-1α protein.
Laboratory for Cytokine Regulation, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama-shi, Kanagawa 230-0045, Japan.|Department of Molecular & Cellular Biology, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd, 6-7-5 Minatojima-Minamimachi, Chuo-Ku, Kobe-shi, Hyogo 650-0047, Japan.
Akiko
A
Matsui-Hasumi
Department of Molecular & Cellular Biology, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd, 6-7-5 Minatojima-Minamimachi, Chuo-Ku, Kobe-shi, Hyogo 650-0047, Japan.
Yayoi
Y
Sato
Laboratory for Cytokine Regulation, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama-shi, Kanagawa 230-0045, Japan.|Department of Molecular & Cellular Biology, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd, 6-7-5 Minatojima-Minamimachi, Chuo-Ku, Kobe-shi, Hyogo 650-0047, Japan.
Ayako
A
Uto-Konomi
Department of Systems Biomedicine, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku,Tokyo 157-8535, Japan.
Satoshi
S
Yamashita
Department of Molecular & Cellular Biology, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd, 6-7-5 Minatojima-Minamimachi, Chuo-Ku, Kobe-shi, Hyogo 650-0047, Japan.
Junji
J
Uehori
Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Akihiko
A
Yoshimura
Department of Immunology, Graduate School of Medicine, Ehime University, Shitsukawa, Toon-shi, Ehime 791-0295, Japan.
Masakatsu
M
Yamashita
Department of Systems Biomedicine, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku,Tokyo 157-8535, Japan.|Department of Systems BioMedicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Hiroshi
H
Asahara
Department of Molecular & Cellular Biology, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd, 6-7-5 Minatojima-Minamimachi, Chuo-Ku, Kobe-shi, Hyogo 650-0047, Japan.
Shinobu
S
Suzuki
Laboratory for Cytokine Regulation, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama-shi, Kanagawa 230-0045, Japan.|Division of Molecular Pathology, Research Institute for Biomedical Science, Tokyo University of Science, 2669 Yamazaki, Noda-shi, Chiba 278-0022, Japan.
Masato
M
Kubo
D000818:Animals; D002454:Cell Differentiation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058504:Th17 Cells / Q000166:cytology* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D044767:Ubiquitin-Protein Ligases
HIF-1; Th17; autoimmune; signaling