TY - JOUR
T1 - A Mammalian Autophagosome Maturation Mechanism Mediated by TECPR1 and the Atg12-Atg5 Conjugate
AU - Chen, Dandan
AU - Fan, Weiliang
AU - Lu, Yiting
AU - Ding, Xiaojun
AU - Chen, She
AU - Zhong, Qing
N1 - Funding Information:
D.C. performed most of the experiments. W.F. and Y.L. helped. X.D. and S.C. performed the mass spectrometry analysis. D.C. and Q.Z. wrote the paper. Q.Z. directed the work. All authors discussed the results and commented on the manuscript. We thank Alice Liang at OCS Microscopy Core of New York University Langone Medical Center for EM analysis and Cell Signaling Technology for TECPR1 antibody production. We also thank all Zhong lab members for helpful discussion, Qiming Sun and Gary Ma for technical assistance, Livy Wilz for the critical reading, and Jeremy Thorner for suggestions. The work is supported by University of California Cancer Research Coordinating Committee funds, a New Investigator Award for Aging from the Ellison Medical Foundation, Hellman Family Fund, American Cancer Society Research Scholar Grant (RSG-11-274-01-CCG), and National Institutes of Health (NIH) R01 (CA133228) to Q.Z.
PY - 2012/3/9
Y1 - 2012/3/9
N2 - Autophagy is a major catabolic pathway in eukaryotes associated with a broad spectrum of human diseases. In autophagy, autophagosomes carrying cellular cargoes fuse with lysosomes for degradation. However, the molecular mechanism underlying autophagosome maturation is largely unknown. Here we report that TECPR1 binds to the Atg12-Atg5 conjugate and phosphatidylinositol 3-phosphate (PtdIns[3]P) to promote autophagosome-lysosome fusion. TECPR1 and Atg16 form mutually exclusive complexes with the Atg12-Atg5 conjugate, and TECPR1 binds PtdIns(3)P upon association with the Atg12-Atg5 conjugate. Strikingly, TECPR1 localizes to and recruits Atg5 to autolysosome membrane. Consequently, elimination of TECPR1 leads to accumulation of autophagosomes and blocks autophagic degradation of LC3-II and p62. Finally, autophagosome maturation marked by GFP-mRFP-LC3 is defective in TECPR1-deficient cells. Thus, we propose that the concerted interactions among TECPR1, Atg12-Atg5, and PtdIns(3)P provide the fusion specificity between autophagosomes and lysosomes and that the assembly of this complex initiates the autophagosome maturation process.
AB - Autophagy is a major catabolic pathway in eukaryotes associated with a broad spectrum of human diseases. In autophagy, autophagosomes carrying cellular cargoes fuse with lysosomes for degradation. However, the molecular mechanism underlying autophagosome maturation is largely unknown. Here we report that TECPR1 binds to the Atg12-Atg5 conjugate and phosphatidylinositol 3-phosphate (PtdIns[3]P) to promote autophagosome-lysosome fusion. TECPR1 and Atg16 form mutually exclusive complexes with the Atg12-Atg5 conjugate, and TECPR1 binds PtdIns(3)P upon association with the Atg12-Atg5 conjugate. Strikingly, TECPR1 localizes to and recruits Atg5 to autolysosome membrane. Consequently, elimination of TECPR1 leads to accumulation of autophagosomes and blocks autophagic degradation of LC3-II and p62. Finally, autophagosome maturation marked by GFP-mRFP-LC3 is defective in TECPR1-deficient cells. Thus, we propose that the concerted interactions among TECPR1, Atg12-Atg5, and PtdIns(3)P provide the fusion specificity between autophagosomes and lysosomes and that the assembly of this complex initiates the autophagosome maturation process.
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U2 - 10.1016/j.molcel.2011.12.036
DO - 10.1016/j.molcel.2011.12.036
M3 - Article
C2 - 22342342
AN - SCOPUS:84862777210
SN - 1097-2765
VL - 45
SP - 629
EP - 641
JO - Molecular cell
JF - Molecular cell
IS - 5
ER -