Nucleobindin 1 controls the unfolded protein response by inhibiting ATF6 activation.
In response to endoplasmic reticulum (ER) stress, activating transcription factor 6 (ATF6), an ER membrane-anchored transcription factor, is transported to the Golgi apparatus and cleaved by site-1 protease (S1P) to activate the unfolded protein response (UPR). Here, we identified nucleobindin 1 (NUCB1) as a novel repressor of the S1P-mediated ATF6 activation. NUCB1 is an ER stress-inducible gene with the promoter region having functional cis-elements for transcriptional activation by ATF6. Overexpression of NUCB1 inhibits S1P-mediated ATF6 cleavage without affecting ER-to-Golgi transport of ATF6, whereas knock-down of NUCB1 by siRNA accelerates ATF6 cleavage during ER stress. NUCB1 protein localizes in the Golgi apparatus, and disruption of the Golgi localization results in loss of the ATF6-inhibitiory activity. Consistent with these observations, NUCB1 can suppress physical interaction of S1P-ATF6 during ER stress. Together, our results demonstrate that NUCB1 is the first-identified, Golgi-localized negative feedback regulator in the ATF6-mediated branch of the UPR.
Tsukumo
Yoshinori
Y
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
Tomida
Akihiro
A
Kitahara
Osamu
O
Nakamura
Yusuke
Y
Asada
Shinichi
S
Mori
Kazutoshi
K
Tsuruo
Takashi
T
D051702:Activating Transcription Factor 6 / Q000737:chemistry* / Q000502:physiology; D001483:Base Sequence; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins; D000080866:Nucleobindins; D011485:Protein Binding; D011489:Protein Denaturation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; C000630649:NUCB1 protein, human; D009419:Nerve Tissue Proteins; D000080866:Nucleobindins; D034741:RNA, Small Interfering