한빛사 논문
고려대학교
Hyun Lee # 1 2, Dong-Min Yu # 1 2, Myeong-Suk Bahn # 1 2, Young-Jae Kwon 1 2, Min Jee Um 1 2, Seo Yeon Yoon 1 2, Ki-Tae Kim 1 2, Myoung-Woo Lee 1 2, Sung-Je Jo 1 2, Sungsoo Lee 1 2, Seung-Hoi Koo 1 2, Ki Hoon Jung 3, Jae-Seon Lee 4, Young-Gyu Ko 5 6
1Tunneling Nanotube Research Center, Korea University, Seoul, 02841, Korea.
2Division of Life Sciences, Korea University, Seoul, 02841, Korea.
3Department of Surgery, Dongguk University College of Medicine, Gyeongju, 38067, Korea.
4Research Center for Controlling Intercellular Communication, College of Medicine, Inha University, Incheon, 22212, Korea.
5Tunneling Nanotube Research Center, Korea University, Seoul, 02841, Korea.
6Division of Life Sciences, Korea University, Seoul, 02841, Korea.
#Contributed equally.
These authors contributed equally: Hyun Lee, Dong-Min Yu, Myeong-Suk Bahn.
Corresponding author: Correspondence to Young-Gyu Ko.
Abstract
Prominin-1 (PROM1), also known as CD133, is expressed in hepatic progenitor cells (HPCs) and cholangiocytes of the fibrotic liver. In this study, we show that PROM1 is upregulated in the plasma membrane of fibrotic hepatocytes. Hepatocellular expression of PROM1 was also demonstrated in mice (Prom1CreER; R26TdTom) in which cells expressed TdTom under control of the Prom1 promoter. To understand the role of hepatocellular PROM1 in liver fibrosis, global and liver-specific Prom1-deficient mice were analyzed after bile duct ligation (BDL). BDL-induced liver fibrosis was aggravated with increased phosphorylation of SMAD2/3 and decreased levels of SMAD7 by global or liver-specific Prom1 deficiency but not by cholangiocyte-specific Prom1 deficiency. Indeed, PROM1 prevented SMURF2-induced SMAD7 ubiquitination and degradation by interfering with the molecular association of SMAD7 with SMURF2. We also demonstrated that hepatocyte-specific overexpression of SMAD7 ameliorated BDL-induced liver fibrosis in liver-specific Prom1-deficient mice. Thus, we conclude that PROM1 is necessary for the negative regulation of TGFβ signaling during liver fibrosis.
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