Autophagy Receptors and Neurodegenerative Diseases Zhiqiang Deng, Kerry Purtell, Veronik Lachance, Mitchell S. Wold, Shi Chen, Zhenyu Yue  Trends in Cell Biology  Volume 27, Issue 7, Pages 491-504 (July 2017) DOI: 10.1016/j.tcb.2017.01.001 Copyright © 2017 Elsevier Ltd Terms and Conditions

Figure 1 Autophagy Process. The process begins with the formation of an isolation membrane (also known as the phagophore), which sequesters cargo, including protein aggregates and intracellular organelles, and expands to form a double-membrane autophagosome. The fully formed autophagosome either fuses with the late endosome to generate an amphisome, or directly fuses with the lysosome to generate an autolysosome to digest and recycle cargo. Trends in Cell Biology 2017 27, 491-504DOI: (10.1016/j.tcb.2017.01.001) Copyright © 2017 Elsevier Ltd Terms and Conditions

Figure 2 Functional Domains and Disease-Associated Mutations in Well-Known Autophagy Receptors. (A) Functional domains of OPTN/optineurin and variants associated with amyotrophic lateral sclerosis (ALS)/frontotemporal lobar degeneration (FTLD). HLX, putative helical domain; CC, coiled-coiled regions; LZ, leucine zippers; LIR, LC3-interacting region; UBAN, Ub-binding domain in ABIN proteins and NEMO; ZF, zinc finger domain. Red indicates mutations that overlap with glaucoma. (B) Functional domains of p62/SQSTM1 and variants associated with ALS/FTLD. PB1, Phox and Bem1 domain; ZZ, zinc finger motif; TRAF6, tumor necrosis factor receptor-associated factor 6; PEST, proline, glutamic acid, serine, and threonine domains; KIR, Keap1 interaction region; UBA, Ub-associated domain. Red indicates mutations that overlap with Paget’s disease of bone (PDB). (C) Functional domains and reported ALS/FTLD-linked mutations of Ubqln 2. UBL, proteasome-binding domain; STI1, heat shock chaperonin-binding motif; PXX, 12-PXX repeat region. (D) Functional domains of other autophagy receptors associated with neurodegenerative disease. NBR1, neighbor of BRCA1 gene 1; NDP52, nuclear dot protein 52kDa; SKICH, skeletal muscle and kidney-enriched inositol phosphatase carboxyl homology domain. Trends in Cell Biology 2017 27, 491-504DOI: (10.1016/j.tcb.2017.01.001) Copyright © 2017 Elsevier Ltd Terms and Conditions

Figure 3 p62/SQSTM1 Modifications and Related Cellular Pathways. p62 is ubiquitinated at K7 by TRIM21 in the PB1 domain, which regulates the Nrf2-mediated antioxidant response. p62 is phosphorylated at T269 and S272 by p38Ð-MEKK3, depending on nutrient availability. Phosphorylated p62 at T269 and S272 promotes p62–TRAF6–mTORC1 complex formation and subsequently activates mTORC1, which regulates cell growth. mTORC1-mediated phosphorylation of p62 at S351 competes for Keap1 binding with Nrf2, and subsequently causes Keap1 degradation via selective autophagy. The escaped Nrf2 enters the nucleus to regulate Nrf2-target gene expression and promote antioxidant response. p62 is phosphorylated at S409 by ULK1, and is subsequently phosphorylated at S405 by TBK1 or CK2. Phosphorylation of p62 in the UBA domain promotes degradation of ubiquitinated proteins in selective autophagy. Amino acid number is based on human p62 sequence, brackets indicate amino acid number of mouse p62. Abbreviations: Keap1, kelch-like ECH-associated protein 1; MEKK3, mitogen-activated protein kinase kinase 3; mTORC1, mammalian target of rapamycin complex 1; Nrf2, nuclear factor erythroid 2-related factor 2; PB1, Phox and Bem1 domain; SQSTM1, Sequestosome 1; TRAF6, tumor necrosis factor receptor-associated factor 6; TRIM21, Tripartite motif-containing protein 21; ULK1, Unc-51 like autophagy activating kinase 1. Trends in Cell Biology 2017 27, 491-504DOI: (10.1016/j.tcb.2017.01.001) Copyright © 2017 Elsevier Ltd Terms and Conditions

Figure 4 OPTN/Optineurin Modifications and Related Cellular Pathways. OPTN is phosphorylated at S177 by Plk1, which reversely regulates the activity of Plk1 during mitosis. However, S177 can be phosphorylated by TBK1 in bacterial-induced autophagy, which enhances its binding affinity with LC3 and promotes autophagic clearance of cytosolic Salmonella. TBK1-mediated phosphorylation of OPTN at S473 in UBAN by TBK1 promotes the clearance of damaged mitochondria in mitophagy. Tumor-suppressor HACE1-mediated ubiquitination of OPTN at Lys193 promotes OPTN interaction with p62 to form an autophagy receptor complex, which recruits more cargoes and targets them to autophagosomes for efficient degradation in selective autophagy. Abbreviations: HACE1, HECT domain and ankyrin repeat containing E3 Ub ligase 1; LC3, microtubule-associated protein 1 light chain 3; Plk1, Polo-like kinase 1; TBK1, Tank-binding kinase 1; UBAN, Ub-binding domain in ABIN proteins and NEMO. Trends in Cell Biology 2017 27, 491-504DOI: (10.1016/j.tcb.2017.01.001) Copyright © 2017 Elsevier Ltd Terms and Conditions