RTN3L and CALCOCO1 function in parallel to maintain proteostasis in the endoplasmic reticulum.
Kamal Kumar1, Ravi Chidambaram1, Smriti Parashar1
1Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA.
Autophagy
|May 31, 2024
Summary
Three receptors, RTN3L, ATL3, and CALCOCO1, maintain endoplasmic reticulum (ER) proteostasis via reticulophagy. RTN3L and ATL3 are crucial for ER-reticulophagy sites (ERPHS) formation, while CALCOCO1 acts in parallel.
Area of Science:
- Cell Biology
- Molecular Biology
- Autophagy Research
Background:
- Reticulophagy, a selective form of autophagy, is crucial for maintaining endoplasmic reticulum (ER) proteostasis.
- Autophagy receptors function within ER tubules or flat sheets, with RTN3L, ATL3, and CALCOCO1 identified as key mediators in ER tubules.
- RTN3L maintains proteostasis by targeting misfolded proteins to ER-reticulophagy sites (ERPHS) within ER tubules.
Purpose of the Study:
- To investigate the roles of ATL3 and CALCOCO1 in proteostasis and their relationship with RTN3L.
- To determine if ATL3 and CALCOCO1 target similar misfolded protein cargoes as RTN3L.
- To elucidate the mechanisms by which these receptors contribute to ER proteostasis.
Main Methods:
- Analysis of three misfolded, disease-causing RTN3L substrates.
- Colocalization studies to assess receptor interactions.
- Knockdown experiments to determine the necessity of each receptor for ERPHS formation.
Main Results:
- ATL3 and CALCOCO1 were found to target the same autophagic cargoes as RTN3L.
- Both RTN3L and ATL3 are essential for the formation of RTN3L-containing ERPHS.
- CALCOCO1 was not required for ERPHS formation, suggesting a distinct but parallel role.
Conclusions:
- RTN3L, ATL3, and CALCOCO1 function in parallel pathways to maintain ER proteostasis.
- RTN3L and ATL3 collaborate in the formation of ERPHS for targeted protein degradation.
- CALCOCO1 contributes to proteostasis through a mechanism independent of ERPHS formation.
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