biostudies-literatureGu SThe National Key Research and Development Program of ChinaThe National Science Foundation of Zhejiang ProvinceThe National Natural Science Foundation of ChinaHangzhou West Lake Pearl Project Leading Innovative Youth Team Project7154-7180https://www.ebi.ac.uk/biostudies/studies/S-EPMC12669696biostudies-literatureUnknown44(23)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, therThe EMBO journalReticulophagy receptor FAM134C restrains BMP receptor signaling.PMC126696963177154631730057LD21C0700012022YFC3401500LZ22C070001TD202301732321002U21A20356Wu JGu SXu PZhao BCao JZhang HLin XLiu TLiu XFeng XHHe ZSun QZheng MHan JJin JYu YfalseReticulophagy 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, ther2025-01-01T00:00:00Z2025 Dec2026-07-15T14:35:42.318Z2026-07-06T03:08:10.554ZS-EPMC126696964111605910.1038/s44318-025-00581-3