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How the principal functions of the Golgi apparatus-protein processing, lipid synthesis, and sorting of macromolecules-are integrated to constitute cargo-specific trafficking pathways originating from the trans-Golgi network (TGN) is unknown. Here, we show that the activity of the Golgi localized SPCA1 calcium pump couples sorting and export of secreted proteins to synthesis of new lipid in the TGN membrane. A secreted Ca-binding protein, Cab45, constitutes the core component of a Ca-dependent, oligomerization-driven sorting mechanism whereby secreted proteins bound to Cab45 are packaged into a TGN-derived vesicular carrier whose membrane is enriched in sphingomyelin, a lipid implicated in TGN-to-cell surface transport. SPCA1 activity is controlled by the sphingomyelin content of the TGN membrane, such that local sphingomyelin synthesis promotes Ca flux into the lumen of the TGN, which drives secretory protein sorting and export, thereby establishing a protein- and lipid-specific secretion pathway.
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http://dx.doi.org/10.1016/j.devcel.2018.10.012 | DOI Listing |
PLoS One
September 2024
Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.
J Invest Dermatol
March 2025
Department of Dermatology, University of Washington, Seattle, Washington, USA; Institute for Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington, USA. Electronic address:
J Biol Chem
August 2024
Department of Medicine, Wilf Family Cardiovascular Research Institute, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York City, New York, USA; Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy; International Transla
The Golgi compartment performs a number of crucial roles in the cell. However, the exact molecular mechanisms underlying these actions are not fully defined. Pathogenic mutations in genes encoding Golgi proteins may serve as an important source for expanding our knowledge.
View Article and Find Full Text PDFIndian J Dermatol Venereol Leprol
November 2024
Department of Dermatology, Yangling Demonstration Zone Hospital, Yangling, China.
Background Hailey-Hailey disease (HHD) is a rare, autosomal dominant, hereditary skin disorder characterised by epidermal acantholysis. The HHD-associated gene ATPase calcium-transporting type 2C member 1 (ATP2C1) encodes the protein secretory pathway Ca2+ ATPase1 (SPCA1), playing a critical role in HHD pathogenesis. Aims We aimed to investigate the effect of ATP2C1 knockdown on keratinocytes that mimicked acantholysis in HHD.
View Article and Find Full Text PDFGlia
June 2024
Department of Cell Biology, Faculty of Sciences, University of Granada, Granada, Spain.
Microglia play an important protective role in the healthy nervous tissue, being able to react to a variety of stimuli that induce different intracellular cascades for specific tasks. Ca signaling can modulate these pathways, and we recently reported that microglial functions depend on the endoplasmic reticulum as a Ca store, which involves the Ca transporter SERCA2b. Here, we investigated whether microglial functions may also rely on the Golgi, another intracellular Ca store that depends on the secretory pathway Ca/Mn-transport ATPase isoform 1 (SPCA1).
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