title: Interplay between Leucine-Rich Repeat Kinase 2 (LRRK2) and p62/SQSTM-1 in Selective Autophagy.
abstract: The deposit of polyubiquitinated aggregates has been implicated in the pathophysiology of Parkinson's disease (PD), and growing evidence indicates that selective autophagy plays a critical role in the clearance of ubiquitin-positive protein aggregates by autophagosomes. The selective autophagic receptor p62/SQSTM-1, which associates directly with both ubiquitin and LC3, transports ubiquitin conjugates to autophagosomes for degradation. Leucine-rich repeat kinase 2 (LRRK2), a PD-associated protein kinase, is tightly controlled by autophagy-lysosome degradation as well as by the ubiquitin-proteasome pathway. However, little is known about the degradation of ubiquitinated LRRK2 via selective autophagy. In the present study, we found that p62/SQSTM-1 physically interacts with LRRK2 as a selective autophagic receptor. The overexpression of p62 leads to the robust degradation of LRRK2 through the autophagy-lysosome pathway. In addition, LRRK2 indirectly regulates Ser351 and Ser403 phosphorylation of p62. Of particular interest, the interaction between phosphorylated p62 and Keap1 is reduced by LRRK2 overexpression. Therefore, we propose that the interplay between LRRK2 and p62 may contribute to the pathophysiological function and homeostasis of LRRK2 protein.
authors.affiliation: Department of Biomedical Laboratory Science, College of Health, Kyungwoon University, Gumi, 39160, South Korea.
authors.forename: Sangwook
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea.|Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, 03080, South Korea.
authors.forename: Seulki
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Pharmacology and Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, 16499, South Korea.
authors.forename: Insup
authors.initials: I
authors.lastname: Choi
authors.affiliation: Department of Pharmacology and Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, 16499, South Korea.
authors.forename: Beomsue
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea.|Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, 03080, South Korea.
authors.forename: Seung Pyo
authors.initials: SP
authors.lastname: Park
authors.affiliation: Department of Pharmacology and Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, 16499, South Korea.
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Joe
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea.|Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, 03080, South Korea.
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Suh
mesh_terms: D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D011247:Pregnancy; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071456:Sequestosome-1 Protein / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D013482:Superoxide Dismutase; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D046988:Proteasome Endopeptidase Complex