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Article: Fluidic shear stress alters clathrin dynamics and vesicle formation in endothelial cells.

Nawara, Tomasz J / Sztul, Elizabeth / Mattheyses, Alexa L

bioRxiv : the preprint server for biology

2024

Abstract: Endothelial cells (ECs) experience a variety of highly dynamic mechanical stresses. Among others, cyclic stretch and increased plasma membrane tension inhibit clathrin-mediated endocytosis (CME) in non-ECs cells. How ECs overcome such unfavorable, from ... ...

Abstract	Endothelial cells (ECs) experience a variety of highly dynamic mechanical stresses. Among others, cyclic stretch and increased plasma membrane tension inhibit clathrin-mediated endocytosis (CME) in non-ECs cells. How ECs overcome such unfavorable, from biophysical perspective, conditions and maintain CME remains elusive. Previously, we have used simultaneous two-wavelength axial ratiometry (STAR) microscopy to show that endocytic dynamics are similar between statically cultured human umbilical vein endothelial cells (HUVECs) and fibroblast-like Cos-7 cells. Here we asked whether biophysical stresses generated by blood flow could favor one mechanism of clathrin-coated vesicle formation to overcome environment present in vasculature. We used our data processing platform - DrSTAR - to examine if clathrin dynamics are altered in HUVECs grown under fluidic sheer stress (FSS). Surprisingly, we found that FSS led to an increase in clathrin dynamics. In HUVECs grown under FSS we observed a 2.3-fold increase in clathrin-coated vesicle formation and a 1.9-fold increase in non-productive flat clathrin lattices compared to cells grown in static conditions. The curvature-positive events had significantly delayed curvature initiation in flow-stimulated cells, highlighting a shift toward flat-to-curved clathrin transitions in vesicle formation. Overall, our findings indicate that clathrin dynamics and CCV formation can be modulated by the local physiological environment and represents an important regulatory mechanism.
Language	English
Publishing date	2024-01-02
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.02.572628
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Article: How can biological modeling help cell biology?

Sztul, Elizabeth

Cellular logistics

2017 Volume 7, Issue 4, Page(s) e1404780

Language	English
Publishing date	2017-11-14
Publishing country	United States
Document type	Editorial
ZDB-ID	2682440-1
ISSN	2159-2799 ; 2159-2780
ISSN (online)	2159-2799
ISSN	2159-2780
DOI	10.1080/21592799.2017.1404780
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Article: Nobel Prize for Cellular Logistics!

Sztul, Elizabeth

Cellular logistics

2013 Volume 3, Page(s) e27194

Language	English
Publishing date	2013-11-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	2682440-1
ISSN	2159-2799 ; 2159-2780
ISSN (online)	2159-2799
ISSN	2159-2780
DOI	10.4161/cl.27194
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Article ; Online: Regulating the regulators: role of phosphorylation in modulating the function of the GBF1/BIG family of Sec7 ARF-GEFs.

Walton, Kendall / Leier, Andre / Sztul, Elizabeth

FEBS letters

2020 Volume 594, Issue 14, Page(s) 2213–2226

Abstract: Membrane traffic between secretory and endosomal compartments is vesicle-mediated and must be tightly balanced to maintain a physiological compartment size. Vesicle formation is initiated by guanine nucleotide exchange factors (GEFs) that activate the ... ...

Abstract	Membrane traffic between secretory and endosomal compartments is vesicle-mediated and must be tightly balanced to maintain a physiological compartment size. Vesicle formation is initiated by guanine nucleotide exchange factors (GEFs) that activate the ARF family of small GTPases. Regulatory mechanisms, including reversible phosphorylation, allow ARF-GEFs to support vesicle formation only at the right time and place in response to cellular needs. Here, we review current knowledge of how the Golgi-specific brefeldin A-resistance factor 1 (GBF1)/brefeldin A-inhibited guanine nucleotide exchange protein (BIG) family of ARF-GEFs is influenced by phosphorylation and use predictive paradigms to propose new regulatory paradigms. We describe a conserved cluster of phosphorylation sites within the N-terminal domains of the GBF1/BIG ARF-GEFs and suggest that these sites may respond to homeostatic signals related to cell growth and division. In the C-terminal region, GBF1 shows phosphorylation sites clustered differently as compared with the similar configuration found in both BIG1 and BIG2. Despite this similarity, BIG1 and BIG2 phosphorylation patterns are divergent in other domains. The different clustering of phosphorylation sites suggests that the nonconserved sites may represent distinct regulatory nodes and specify the function of GBF1, BIG1, and BIG2.
MeSH term(s)	Animals ; Guanine Nucleotide Exchange Factors/chemistry ; Guanine Nucleotide Exchange Factors/metabolism ; Humans ; Phosphoproteins/chemistry ; Phosphoproteins/metabolism ; Phosphorylation
Chemical Substances	ARFGEF1 protein, human ; ARFGEF2 protein, human ; GBF1 protein, human ; Guanine Nucleotide Exchange Factors ; Phosphoproteins ; Sec7 guanine nucleotide exchange factors
Language	English
Publishing date	2020-05-14
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1002/1873-3468.13798
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Article ; Online: Site-specific phosphorylations of the Arf activator GBF1 differentially regulate GBF1 function in Golgi homeostasis and secretion versus cytokinesis.

Walton, Kendall / Nawara, Tomasz J / Angermeier, Allyson R / Rosengrant, Hadley / Lee, Eunjoo / Wynn, Bridge / Victorova, Ekaterina / Belov, George / Sztul, Elizabeth

Scientific reports

2023 Volume 13, Issue 1, Page(s) 13609

Abstract: Diverse cellular processes, including membrane traffic, lipid homeostasis, cytokinesis, mitochondrial positioning, and cell motility are critically dependent on the Sec7 domain guanine nucleotide exchange factor GBF1. Yet, how the participation of GBF1 ... ...

Abstract	Diverse cellular processes, including membrane traffic, lipid homeostasis, cytokinesis, mitochondrial positioning, and cell motility are critically dependent on the Sec7 domain guanine nucleotide exchange factor GBF1. Yet, how the participation of GBF1 in a particular cellular function is regulated is unknown. Here, we show that the phosphorylation of specific highly conserved serine and tyrosine residues within the N-terminal domain of GBF1 differentially regulates its function in maintaining Golgi homeostasis and facilitating secretion versus its role in cytokinesis. Specifically, GBF1 mutants containing single amino acid substitutions that mimic a stably phosphorylated S233, S371, Y377, and Y515 or the S233A mutant that can't be phosphorylated are fully able to maintain Golgi architecture and support cargo traffic through the secretory pathway when assessed in multiple functional assays. However, the same mutants cause multi-nucleation when expressed in cells, and appear to inhibit the progression through mitosis and the resolution of cytokinetic bridges. Thus, GBF1 participates in distinct interactive networks when mediating Golgi homeostasis and secretion versus facilitating cytokinesis, and GBF1 integration into such networks is differentially regulated by the phosphorylation of specific GBF1 residues.
MeSH term(s)	Cytokinesis ; Phosphorylation ; Golgi Apparatus ; Amino Acid Substitution ; Homeostasis
Language	English
Publishing date	2023-08-21
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-40705-5
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Article ; Online: The development of resistance to an inhibitor of a cellular protein reveals a critical interaction between the enterovirus protein 2C and a small GTPase Arf1.

Viktorova, Ekaterina G / Gabaglio, Samuel / Moghimi, Seyedehmahsa / Zimina, Anna / Wynn, Bridge G / Sztul, Elizabeth / Belov, George A

PLoS pathogens

2023 Volume 19, Issue 9, Page(s) e1011673

Abstract: The cellular protein GBF1, an activator of Arf GTPases (ArfGEF: Arf guanine nucleotide exchange factor), is recruited to the replication organelles of enteroviruses through interaction with the viral protein 3A, and its ArfGEF activity is required for ... ...

Abstract	The cellular protein GBF1, an activator of Arf GTPases (ArfGEF: Arf guanine nucleotide exchange factor), is recruited to the replication organelles of enteroviruses through interaction with the viral protein 3A, and its ArfGEF activity is required for viral replication, however how GBF1-dependent Arf activation supports the infection remains enigmatic. Here, we investigated the development of resistance of poliovirus, a prototype enterovirus, to increasing concentrations of brefeldin A (BFA), an inhibitor of GBF1. High level of resistance required a gradual accumulation of multiple mutations in the viral protein 2C. The 2C mutations conferred BFA resistance even in the context of a 3A mutant previously shown to be defective in the recruitment of GBF1 to replication organelles, and in cells depleted of GBF1, suggesting a GBF1-independent replication mechanism. Still, activated Arfs accumulated on the replication organelles of this mutant even in the presence of BFA, its replication was inhibited by a pan-ArfGEF inhibitor LM11, and the BFA-resistant phenotype was compromised in Arf1-knockout cells. Importantly, the mutations strongly increased the interaction of 2C with the activated form of Arf1. Analysis of other enteroviruses revealed a particularly strong interaction of 2C of human rhinovirus 1A with activated Arf1. Accordingly, the replication of this virus was significantly less sensitive to BFA than that of poliovirus. Thus, our data demonstrate that enterovirus 2Cs may behave like Arf1 effector proteins and that GBF1 but not Arf activation can be dispensable for enterovirus replication. These findings have important implications for the development of host-targeted anti-viral therapeutics.
MeSH term(s)	Humans ; Enterovirus/metabolism ; Monomeric GTP-Binding Proteins/metabolism ; ADP-Ribosylation Factor 1/genetics ; ADP-Ribosylation Factor 1/metabolism ; HeLa Cells ; Poliovirus/genetics ; Viral Proteins/metabolism ; Enterovirus Infections ; Antigens, Viral/metabolism ; Brefeldin A/pharmacology ; Guanine Nucleotide Exchange Factors/genetics ; Guanine Nucleotide Exchange Factors/metabolism
Chemical Substances	Monomeric GTP-Binding Proteins (EC 3.6.5.2) ; ADP-Ribosylation Factor 1 (EC 3.6.5.2) ; Viral Proteins ; Antigens, Viral ; Brefeldin A (20350-15-6) ; GBF1 protein, human ; Guanine Nucleotide Exchange Factors
Language	English
Publishing date	2023-09-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011673
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Article ; Online: Modeling the dynamic behaviors of the COPI vesicle formation regulators, the small GTPase Arf1 and its activating Sec7 guanine nucleotide exchange factor GBF1 on Golgi membranes.

Sager, Garrett / Szul, Tomasz / Lee, Eunjoo / Kawai, Ryoichi / Presley, John F / Sztul, Elizabeth

Molecular biology of the cell

2021 Volume 32, Issue 5, Page(s) 446–459

Abstract: The components and subprocesses underlying the formation of COPI-coated vesicles at the Golgi are well understood. The coating cascade is initiated after the small GTPase Arf1 is activated by the Sec7 domain-containing guanine nucleotide exchange factor ... ...

Abstract	The components and subprocesses underlying the formation of COPI-coated vesicles at the Golgi are well understood. The coating cascade is initiated after the small GTPase Arf1 is activated by the Sec7 domain-containing guanine nucleotide exchange factor GBF1 (Golgi brefeldin A resistant guanine nucleotide exchange factor 1). This causes a conformational shift within Arf1 that facilitates stable association of Arf1 with the membrane, a process required for subsequent recruitment of the COPI coat. Although we have atomic-level knowledge of Arf1 activation by Sec7 domain-containing GEFs, our understanding of the biophysical processes regulating Arf1 and GBF1 dynamics is limited. We used fluorescence recovery after photobleaching data and kinetic Monte Carlo simulation to assess the behavior of Arf1 and GBF1 during COPI vesicle formation in live cells. Our analyses suggest that Arf1 and GBF1 associate with Golgi membranes independently, with an excess of GBF1 relative to Arf1. Furthermore, the GBF1-mediated Arf1 activation is much faster than GBF1 cycling on/off the membrane, suggesting that GBF1 is regulated by processes other than its interactions Arf1. Interestingly, modeling the behavior of the catalytically inactive GBF1/E794K mutant stabilized on the membrane is inconsistent with the formation of a stable complex between it and an endogenous Arf1 and suggests that GBF1/E794K is stabilized on the membrane independently of complex formation.
MeSH term(s)	ADP-Ribosylation Factor 1/metabolism ; ADP-Ribosylation Factor 1/physiology ; ADP-Ribosylation Factors/metabolism ; COP-Coated Vesicles/metabolism ; COP-Coated Vesicles/physiology ; Coat Protein Complex I/metabolism ; Endocytosis ; Endoplasmic Reticulum/metabolism ; Fluorescence Recovery After Photobleaching/methods ; Golgi Apparatus/metabolism ; Guanine Nucleotide Exchange Factors/metabolism ; Guanine Nucleotide Exchange Factors/physiology ; HeLa Cells ; Humans ; Kinetics ; Monomeric GTP-Binding Proteins/metabolism ; Monte Carlo Method ; Protein Binding ; Protein Transport
Chemical Substances	Coat Protein Complex I ; GBF1 protein, human ; Guanine Nucleotide Exchange Factors ; Sec7 guanine nucleotide exchange factors ; ADP-Ribosylation Factor 1 (EC 3.6.5.2) ; ADP-Ribosylation Factors (EC 3.6.5.2) ; ARF1 protein, human (EC 3.6.5.2) ; Monomeric GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2021-01-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1098979-1
ISSN	1939-4586 ; 1059-1524
ISSN (online)	1939-4586
ISSN	1059-1524
DOI	10.1091/mbc.E20-09-0587
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Zs.A 2853: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 410: Show issues

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Article: Finding your inner modeler: An NSF-sponsored workshop to introduce cell biologists to modeling/computational approaches.

Stone, David E / Haswell, Elizabeth S / Sztul, Elizabeth

Cellular logistics

2017 Volume 7, Issue 4, Page(s) e1382669

Abstract: In classical Cell Biology, fundamental cellular processes are revealed empirically, one experiment at a time. While this approach has been enormously fruitful, our understanding of cells is far from complete. In fact, the more we know, the more keenly we ...

Abstract	In classical Cell Biology, fundamental cellular processes are revealed empirically, one experiment at a time. While this approach has been enormously fruitful, our understanding of cells is far from complete. In fact, the more we know, the more keenly we perceive our ignorance of the profoundly complex and dynamic molecular systems that underlie cell structure and function. Thus, it has become apparent to many cell biologists that experimentation alone is unlikely to yield major new paradigms, and that empiricism must be combined with theory and computational approaches to yield major new discoveries. To facilitate those discoveries, three workshops will convene annually for one day in three successive summers (2017-2019) to promote the use of computational modeling by cell biologists currently unconvinced of its utility or unsure how to apply it. The first of these workshops was held at the University of Illinois, Chicago in July 2017. Organized to facilitate interactions between traditional cell biologists and computational modelers, it provided a unique educational opportunity: a primer on how cell biologists with little or no relevant experience can incorporate computational modeling into their research. Here, we report on the workshop and describe how it addressed key issues that cell biologists face when considering modeling including: (1) Is my project appropriate for modeling? (2) What kind of data do I need to model my process? (3) How do I find a modeler to help me in integrating modeling approaches into my work? And, perhaps most importantly, (4) why should I bother?
Language	English
Publishing date	2017-09-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2682440-1
ISSN	2159-2799 ; 2159-2780
ISSN (online)	2159-2799
ISSN	2159-2780
DOI	10.1080/21592799.2017.1382669
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Article ; Online: Commonly used trafficking blocks disrupt ARF1 activation and the localization and function of specific Golgi proteins.

Gilbert, Catherine E / Sztul, Elizabeth / Machamer, Carolyn E

Molecular biology of the cell

2018 Volume 29, Issue 8, Page(s) 937–947

Abstract: Cold temperature blocks used to synchronize protein trafficking inhibit GBF1 function, leading to a decrease in ARF1-GTP levels and mislocalization of the ARF1 effector golgin-160. Several other, but not all, Golgi proteins including ARL1 also ... ...

Abstract	Cold temperature blocks used to synchronize protein trafficking inhibit GBF1 function, leading to a decrease in ARF1-GTP levels and mislocalization of the ARF1 effector golgin-160. Several other, but not all, Golgi proteins including ARL1 also mislocalize. ARF1 activity and golgin-160 localization require more than 30 min to recover from these blocks.
MeSH term(s)	ADP-Ribosylation Factor 1/genetics ; ADP-Ribosylation Factor 1/metabolism ; Autoantigens/genetics ; Autoantigens/metabolism ; Cold Temperature ; Golgi Matrix Proteins/genetics ; Golgi Matrix Proteins/metabolism ; Guanine Nucleotide Exchange Factors/antagonists & inhibitors ; Guanine Nucleotide Exchange Factors/metabolism ; HeLa Cells ; Humans ; Protein Transport ; trans-Golgi Network/metabolism
Chemical Substances	Autoantigens ; GBF1 protein, human ; GOLGA3 protein, human ; Golgi Matrix Proteins ; Guanine Nucleotide Exchange Factors ; ADP-Ribosylation Factor 1 (EC 3.6.5.2)
Language	English
Publishing date	2018-03-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1098979-1
ISSN	1939-4586 ; 1059-1524
ISSN (online)	1939-4586
ISSN	1059-1524
DOI	10.1091/mbc.E17-11-0622
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Zs.A 2853: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 410: Show issues

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Article ; Online: Imaging vesicle formation dynamics supports the flexible model of clathrin-mediated endocytosis.

Nawara, Tomasz J / Williams, Yancey D / Rao, Tejeshwar C / Hu, Yuesong / Sztul, Elizabeth / Salaita, Khalid / Mattheyses, Alexa L

Nature communications

2022 Volume 13, Issue 1, Page(s) 1732

Abstract: Clathrin polymerization and changes in plasma membrane architecture are necessary steps in forming vesicles to internalize cargo during clathrin-mediated endocytosis (CME). Simultaneous analysis of clathrin dynamics and membrane structure is challenging ... ...

Abstract	Clathrin polymerization and changes in plasma membrane architecture are necessary steps in forming vesicles to internalize cargo during clathrin-mediated endocytosis (CME). Simultaneous analysis of clathrin dynamics and membrane structure is challenging due to the limited axial resolution of fluorescence microscopes and the heterogeneity of CME. This has fueled conflicting models of vesicle assembly and obscured the roles of flat clathrin assemblies. Here, using Simultaneous Two-wavelength Axial Ratiometry (STAR) microscopy, we bridge this critical knowledge gap by quantifying the nanoscale dynamics of clathrin-coat shape change during vesicle assembly. We find that de novo clathrin accumulations generate both flat and curved structures. High-throughput analysis reveals that the initiation of vesicle curvature does not directly correlate with clathrin accumulation. We show clathrin accumulation is preferentially simultaneous with curvature formation at shorter-lived clathrin-coated vesicles (CCVs), but favors a flat-to-curved transition at longer-lived CCVs. The broad spectrum of curvature initiation dynamics revealed by STAR microscopy supports multiple productive mechanisms of vesicle formation and advocates for the flexible model of CME.
MeSH term(s)	Cell Membrane/metabolism ; Clathrin/metabolism ; Clathrin-Coated Vesicles/metabolism ; Endocytosis ; Microscopy, Fluorescence
Chemical Substances	Clathrin
Language	English
Publishing date	2022-04-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-29317-1
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