Golgi pH and Ion Homeostasis in Health and Disease
Maintenance of the main Golgi functions, glycosylation and sorting, is dependent on the unique Golgi pH microenvironment that is thought to be set by the balance between the rates of V-ATPase-mediated proton pumping and its leakage back to the cytoplasm v
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Golgi pH and Ion Homeostasis in Health and Disease Elham Khosrowabadi and Sakari Kellokumpu
Contents 1 Introduction 2 Maintenance of Golgi pH Homeostasis 2.1 Golgi Acidification by the V-ATPase 2.2 Counter Ion Transport 2.3 Proton Leakage Pathway 2.4 Golgi Homeostasis of Other Ions 3 Diseases Associated with Altered Golgi pH and Ion Homeostasis 3.1 Autosomal Recessive Cutis Laxa Type II 3.2 Cancers 3.3 Viral Infections 3.4 Multigenerational Non-syndromic Intellectual Disability (ID) 3.5 Angelman Syndrome and Autism Spectrum Disorders 3.6 Hailey-Hailey Disease 3.7 Congenital Disorder of Glycosylation 2K (CDG2K) 3.8 Menkes Disease and Related Syndromes 4 Perspectives and Key Questions References
Abstract Maintenance of the main Golgi functions, glycosylation and sorting, is dependent on the unique Golgi pH microenvironment that is thought to be set by the balance between the rates of V-ATPase-mediated proton pumping and its leakage back to the cytoplasm via an unknown pathway. The concentration of other ions, such as chloride, potassium, calcium, magnesium, and manganese, is also important for Golgi homeostasis and dependent on the transport activity of other ion transporters present in the Golgi membranes. During the last decade, several new Author Contributions: E. Khosrowabadi and S. Kellokumpu both participated in writing and reviewing of the final manuscript. E. Khosrowabadi made the figures and edited the references and the text; S. Kellokumpu made final revisions to the text. E. Khosrowabadi and S. Kellokumpu (*) Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland e-mail: elham.khosrowabadi@oulu.fi; sakari.kellokumpu@oulu.fi
E. Khosrowabadi and S. Kellokumpu
disorders have been identified that are caused by, or are associated with, dysregulated Golgi pH and ion homeostasis. Here, we will provide an updated overview on these disorders and the proteins involved. We will also discuss other disorders for which the molecular defects remain currently uncertain but which potentially involve proteins that regulate Golgi pH or ion homeostasis. Keywords Disease · Golgi dysfunction · Golgi homeostasis · Ion balance · Resting pH
1 Introduction The pH of secretory and endocytic compartments is known to be uniquely acidic in each compartment and crucial for their efficient functioning in mammalian cells (Kim et al. 1996; Demaurex et al. 1998; Palokangas et al. 1998; Schapiro and Grinstein 2000; Wu et al. 2001; Paroutis et al. 2004, for a recent review, see also Kellokumpu 2019). In general, the acidity of the secretory compartments increases toward the plasma membrane, while the pH of endosomal compartments increases toward the cell center (late endosomes and lysosomes). Among all these compartments, the Golgi apparatus is the most enigmatic one, as it represents a converging point between the two pathways, receiving vesicular carriers from the endoplasmic reticulum (neutral) and the endosomal compartments (acidic) and sending them back to these destinations as part of its sorting functions. Moreo
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