Reticulophagy receptor FAM134C restrains BMP receptor signaling

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.

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Publication Details

Journal
The EMBO Journal
Published
2025-10-20
DOI
https://doi.org/10.1038/s44318-025-00581-3
Primary Topic
Autophagy in Disease and Therapy
Type
article
Field-Weighted Citation Impact
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article

Reticulophagy receptor FAM134C restrains BMP receptor signaling

Jianping Jin, Pinglong Xu, Mingjie Zheng, Jianfeng Wu et al.
The EMBO Journal
Autophagy in Disease and Therapy
article

Reticulophagy receptor FAM134C restrains BMP receptor signaling

Jianping Jin, Pinglong Xu, Mingjie Zheng, Jianfeng Wu, Hanchenxi Zhang, Xin‐Hua Feng, Xia Lin, Qiming Sun, Yi Yu, Jiahuai Han, Bin Zhao, Jin Cao, Xia Liu, Zhou He, Ting Liu, Shuchen Gu
article en

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.

The EMBO JournalVol. 44(23)
Zhejiang International Studies University (CN), Xiamen University (CN), Shaoxing University (CN), Zhejiang Cancer Hospital (CN), Zhejiang Lab (CN), Second Affiliated Hospital of Zhejiang University (CN), Center for Life Sciences (CN), First Affiliated Hospital Zhejiang University (CN), Zhejiang University (CN)
Openalex Percentile: Top 60%
Autophagy in Disease and Therapy
DOIOpen Access PDFOpenAlex
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