2. Academic Validation
  3. Reticulophagy receptor FAM134C restrains BMP receptor signaling

Reticulophagy receptor FAM134C restrains BMP receptor signaling

  • EMBO J. 2025 Oct 20. doi: 10.1038/s44318-025-00581-3.
Shuchen Gu # 1 2 3,  Hanchenxi Zhang # 4,  Jin Cao 4 5 6,  Zhou He 4,  Jianfeng Wu 7,  Xia Liu 8,  Mingjie Zheng 4,  Ting Liu 4 9,  Bin Zhao 4 6,  Pinglong Xu 4 6,  Qiming Sun 10 11,  Jianping Jin 4 6,  Xia Lin 12,  Yi Yu 4 5 6,  Jiahuai Han 7,  Xin-Hua Feng 13 14 15 16
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Key Laboratory of Molecular Cancer Biology, Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, 310058, China. fenglab@zju.edu.cn.
  • 2 Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang, 321000, China. fenglab@zju.edu.cn.
  • 3 Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China. fenglab@zju.edu.cn.
  • 4 MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Key Laboratory of Molecular Cancer Biology, Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 5 Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang, 321000, China.
  • 6 Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 7 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361005, China.
  • 8 ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, Zhejiang, 311215, China.
  • 9 School of Basic Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 10 International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University, Yiwu, Zhejiang, 322000, China.
  • 11 The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, 310009, China.
  • 12 Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China.
  • 13 MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Key Laboratory of Molecular Cancer Biology, Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, 310058, China. xhfeng@zju.edu.cn.
  • 14 Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang, 321000, China. xhfeng@zju.edu.cn.
  • 15 Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China. xhfeng@zju.edu.cn.
  • 16 The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, 310009, China. xhfeng@zju.edu.cn.
  • # Contributed equally.
PMID: 41116059 DOI: 10.1038/s44318-025-00581-3
Abstract

FAM134/RETREG family members are ER-phagy receptors that maintain cellular homeostasis by regulating endoplasmic reticulum turnover. However, possible non-ER-phagy functions of FAM134 proteins remain elusive. Here, we show that RETREG3/FAM134C functions as a selective Autophagy receptor for the type I BMP Receptor (BMPRIA/ALK3) and recruits BMPRIA into LC3-containing autophagosomes for subsequent degradation. FAM134C-induced degradation diminishes the availability of BMP receptors and thus the strength of BMP signaling. Inhibition of Autophagy through chemical means or knockdown of key Autophagy regulators, ATG5 or Beclin-1, prevents BMPR1A degradation. Additionally, disruption of the putative LC3-interacting region (LIR) motif in FAM134C completely abolishes its interaction with LC3, thereby impeding its ability to degrade BMPR1A. Moreover, FAM134C-deficient mice exhibit enhanced BMP responses in the intestines, which affects intestinal crypt regeneration. Our findings suggest that FAM134C acts as a specific receptor that controls BMP signaling through the autophagic degradation of the type I BMP Receptor, independent of its canonical role in ER-phagy.

Keywords

Autophagy; Degradation; RETREG; Smad; TGF-β.

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