title: Sequestosome1/p62: a regulator of redox-sensitive voltage-activated potassium channels, arterial remodeling, inflammation, and neurite outgrowth.
abstract: Sequestosome1/p62 (SQSTM1) is an oxidative stress-inducible protein regulated by the redox-sensitive transcription factor Nrf2. It is not an antioxidant but known as a multifunctional regulator of cell signaling with an ability to modulate targeted or selective degradation of proteins through autophagy. SQSTM1 implements these functions through physical interactions with different types of proteins including atypical PKCs, nonreceptor-type tyrosine kinase p56(Lck) (Lck), polyubiquitin, and autophagosomal factor LC3. One of the notable physiological functions of SQSTM1 is the regulation of redox-sensitive voltage-gated potassium (Kv) channels which are composed of α and β subunits: (Kvα)4 (Kvβ)4. Previous studies have established that SQSTM1 scaffolds PKCζ, enhancing phosphorylation of Kvβ which induces inhibition of pulmonary arterial Kv1.5 channels under acute hypoxia. Recent studies reveal that Lck indirectly interacts with Kv1.3 α subunits and plays a key role in acute hypoxia-induced Kv1.3 channel inhibition in T lymphocytes. Kv1.3 channels provide a signaling platform to modulate the migration and proliferation of arterial smooth muscle cells and activation of T lymphocytes, and hence have been recognized as a therapeutic target for treatment of restenosis and autoimmune diseases. In this review, we focus on the functional interactions of SQSTM1 with Kv channels through two key partners aPKCs and Lck. Furthermore, we provide molecular insights into the functions of SQSTM1 in suppression of proliferation of arterial smooth muscle cells and neointimal hyperplasia following carotid artery ligation, in T lymphocyte differentiation and activation, and in NGF-induced neurite outgrowth in PC12 cells.
authors.affiliation: School of Medicine, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki, 305-8575, Japan. Electronic address: ishiitetsuro305@gmail.com.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ishii
authors.affiliation: School of Medicine, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki, 305-8575, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Warabi
authors.affiliation: Cardiovascular Division, British Heart Foundation Centre of Research Excellence, School of Medicine, King's College London, London SE1 9NH, UK.
authors.forename: Richard C M
authors.initials: RCM
authors.lastname: Siow
authors.affiliation: Cardiovascular Division, British Heart Foundation Centre of Research Excellence, School of Medicine, King's College London, London SE1 9NH, UK.
authors.forename: Giovanni E
authors.initials: GE
authors.lastname: Mann
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001158:Arteries / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D016501:Neurites / Q000378:metabolism*; D010084:Oxidation-Reduction; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D066253:Vascular Remodeling / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D024642:Potassium Channels, Voltage-Gated; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein
keywords: 4-hydroxynonenal; AP-1; ARE; Arterial smooth muscle cells; CDK; EGF; ERK1/2; HNE; HO-1; IL-1; K(v); K(v) channels; Keap1; Kelch-like ECH associated protein 1; Lck; MAPK; NF-κB; NGF; Neointimal hyperplasia; Neurite outgrowth; Nrf2; PASMCs; PDB; PKCζ; PKCλ/ι; Pajet's disease of bone; Prx1; ROS; SAP97; SMCs; SQSTM1; Sequestosome1; T cell receptor; T helper 2; T lymphocytes; TCR; TXA(2); Th2; UBA; ZIP; aPKC; activator protein-1; antioxidant response element; atypical protein kinase C; cyclin-dependent kinase; epidermal growth factor; extracellular regulated kinase 1/2; heme oxygenase-1; interleukin-1; mitogen-activated protein kinase; nerve growth factor; nonreceptor-type tyrosine kinase p56(Lck); nuclear factor erythroid 2-related factor 2; nuclear factor kappa beta; oxLDL; oxidized low density lipoprotein; p56Lck; p62; peroxiredoxin 1; protein kinase C rambda or iota; protein kinase C zeta; pulmonary artery smooth muscle cells; reactive oxygen species; sequestosome1; smooth muscle cells; synapse-associated protein 97; thromboxane A(2); ubiquitin association; voltage-gated potassium channel; zeta-interacting protein