title: Adaptation of endoplasmic reticulum exit sites to acute and chronic increases in cargo load.
abstract: The biogenesis of endoplasmic reticulum (ER) exit sites (ERES) involves the formation of phosphatidylinositol-4 phosphate (PI4) and Sec16, but it is entirely unknown how ERES adapt to variations in cargo load. Here, we studied acute and chronic adaptive responses of ERES to an increase in cargo load for ER export. The acute response (within minutes) to increased cargo load stimulated ERES fusion events, leading to larger but less ERES. Silencing either PI4-kinase IIIalpha (PI4K-IIIalpha) or Sec16 inhibited the acute response. Overexpression of secretory cargo for 24 h induced the unfolded protein response (UPR), upregulated COPII, and the cells formed more ERES. This chronic response was insensitive to silencing PI4K-IIIalpha, but was abrogated by silencing Sec16. The UPR was required as the chronic response was absent in cells lacking inositol-requiring protein 1. Mathematical model simulations further support the notion that increasing ERES number together with COPII levels is an efficient way to enhance the secretory flux. These results indicate that chronic and acute increases in cargo load are handled differentially by ERES and are regulated by different factors.
authors.affiliation: Department of Pharmacology & Neurobiology, Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Hesso
authors.initials: H
authors.lastname: Farhan
authors.forename: Matthias
authors.initials: M
authors.lastname: Weiss
authors.forename: Katsuko
authors.initials: K
authors.lastname: Tani
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hauri
mesh_terms: D022181:COP-Coated Vesicles / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000502:physiology*; D006056:Golgi Apparatus / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology*; D015778:Minor Histocompatibility Antigens; D008954:Models, Biological; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor); D017510:Protein Folding; D021381:Protein Transport; D022142:Secretory Vesicles / Q000502:physiology*; D015398:Signal Transduction; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D015778:Minor Histocompatibility Antigens; D018129:Phosphatidylinositol Phosphates; C517555:SEC16A protein, human; D033921:Vesicular Transport Proteins; C037178:phosphatidylinositol 4-phosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C402182:phosphatidylinositol phosphate 4-kinase