Autophagy inhibitor LRPPRC suppresses mitophagy through interaction with mitophagy initiator Parkin.
Autophagy plays an important role in tumorigenesis. Mitochondrion-associated protein LRPPRC interacts with MAP1S that interacts with LC3 and bridges autophagy components with microtubules and mitochondria to affect autophagy flux. Dysfunction of LRPPRC and MAP1S is associated with poor survival of ovarian cancer patients. Furthermore, elevated levels of LRPPRC predict shorter overall survival in patients with prostate adenocarcinomas or gastric cancer. To understand the role of LRPPRC in tumor development, previously we reported that LRPPRC forms a ternary complex with Beclin 1 and Bcl-2 to inhibit autophagy. Here we further show that LRPPRC maintains the stability of Parkin that mono-ubiquitinates Bcl-2 to increase Bcl-2 stability to inhibit autophagy. Under mitophagy stress, Parkin translocates to mitochondria to cause rupture of outer mitochondrial membrane and bind with exposed LRPPRC. Consequently, LRPPRC and Parkin help mitochondria being engulfed in autophagosomes to be degraded. In cells under long-term mitophagy stress, both LRPPRC and Parkin become depleted coincident with disappearance of mitochondria and final autophagy inactivation due to depletion of ATG5-ATG12 conjugates. LRPPRC functions as a checkpoint protein that prevents mitochondria from autophagy degradation and impact tumorigenesis.
Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas, United States of America; Jiangxi Research Institute of Ophthalmology and Visual Sciences, The Affiliated Eye Hospital of Nanchang University, Nanchang, Jiangxi, China.
Jing
J
Zou
Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas, United States of America.
Fei
F
Yue
Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas, United States of America.
Wenjiao
W
Li
Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas, United States of America.
Kun
K
Song
Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas, United States of America.
Xianhan
X
Jiang
Jiangxi Research Institute of Ophthalmology and Visual Sciences, The Affiliated Eye Hospital of Nanchang University, Nanchang, Jiangxi, China.
Jinglin
J
Yi
Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas, United States of America.
Leyuan
L
Liu
D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D063646:Carcinogenesis / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D063306:Mitophagy / Q000502:physiology*; D009363:Neoplasm Proteins / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C000595707:BCL2 protein, human; C491997:BECN1 protein, human; D000071186:Beclin-1; C087940:LRPPRC protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein