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
  • 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. [email protected].
  • 2. Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang, 321000, China. [email protected].
  • 3. Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China. [email protected].
  • 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. [email protected].
  • 14. Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang, 321000, China. [email protected].
  • 15. Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China. [email protected].
  • 16. The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, 310009, China. [email protected].
  • # 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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