| Structural highlights
Function
TCPR1_HUMAN Tethering factor involved in autophagy. Involved in autophagosome maturation by promoting the autophagosome fusion with lysosomes: acts by associating with both the ATG5-ATG12 conjugate and phosphatidylinositol-3-phosphate (PtdIns(3)P) present at the surface of autophagosomes. Also involved in selective autophagy against bacterial pathogens, by being required for phagophore/preautophagosomal structure biogenesis and maturation.[1] [2]
Publication Abstract from PubMed
Invasive bacteria enter the cytosol of host cells through initial uptake into bacteria-containing vacuoles (BCVs) and subsequent rupture of the BCV membrane, thereby exposing to the cytosol intraluminal, otherwise shielded danger signals such as glycans and sphingomyelin. The detection of glycans by galectin-8 triggers anti-bacterial autophagy, but how cells sense and respond to cytosolically exposed sphingomyelin remains unknown. Here, we identify TECPR1 (tectonin beta-propeller repeat containing 1) as a receptor for cytosolically exposed sphingomyelin, which recruits ATG5 into an E3 ligase complex that mediates lipid conjugation of LC3 independently of ATG16L1. TECPR1 binds sphingomyelin through its N-terminal DysF domain (N'DysF), a feature not shared by other mammalian DysF domains. Solving the crystal structure of N'DysF, we identified key residues required for the interaction, including a solvent-exposed tryptophan (W154) essential for binding to sphingomyelin-positive membranes and the conjugation of LC3 to lipids. Specificity of the ATG5/ATG12-E3 ligase responsible for the conjugation of LC3 is therefore conferred by interchangeable receptor subunits, that is, the canonical ATG16L1 and the sphingomyelin-specific TECPR1, in an arrangement reminiscent of certain multi-subunit ubiquitin E3 ligases.
TECPR1 conjugates LC3 to damaged endomembranes upon detection of sphingomyelin exposure.,Boyle KB, Ellison CJ, Elliott PR, Schuschnig M, Grimes K, Dionne MS, Sasakawa C, Munro S, Martens S, Randow F EMBO J. 2023 Jul 6:e113012. doi: 10.15252/embj.2022113012. PMID:37409490[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ogawa M, Yoshikawa Y, Kobayashi T, Mimuro H, Fukumatsu M, Kiga K, Piao Z, Ashida H, Yoshida M, Kakuta S, Koyama T, Goto Y, Nagatake T, Nagai S, Kiyono H, Kawalec M, Reichhart JM, Sasakawa C. A Tecpr1-dependent selective autophagy pathway targets bacterial pathogens. Cell Host Microbe. 2011 May 19;9(5):376-89. doi: 10.1016/j.chom.2011.04.010. PMID:21575909 doi:http://dx.doi.org/10.1016/j.chom.2011.04.010
- ↑ Chen D, Fan W, Lu Y, Ding X, Chen S, Zhong Q. A mammalian autophagosome maturation mechanism mediated by TECPR1 and the Atg12-Atg5 conjugate. Mol Cell. 2012 Mar 9;45(5):629-41. doi: 10.1016/j.molcel.2011.12.036. Epub 2012, Feb 16. PMID:22342342 doi:http://dx.doi.org/10.1016/j.molcel.2011.12.036
- ↑ Boyle KB, Ellison CJ, Elliott PR, Schuschnig M, Grimes K, Dionne MS, Sasakawa C, Munro S, Martens S, Randow F. TECPR1 conjugates LC3 to damaged endomembranes upon detection of sphingomyelin exposure. EMBO J. 2023 Jul 6:e113012. PMID:37409490 doi:10.15252/embj.2022113012
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