Protein folding does not prevent the nonclassical export of FGF1 and S100A13

Graziani, Irene; Doyle, Andrew W.; Sterling, Sarah M.; Kirov, Alek; Tarantini, Francesca; Landriscina, Matteo; Kumar, Thallapuranam Krishnaswamy Suresh; Neivandt, David J.; Prudovsky, Igor

doi:10.1016/j.bbrc.2009.02.061

Cited by 10 publications

(13 citation statements)

References 53 publications

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“…Non-conventional -Accumulate at the plasma membrane and induce the formation of exosomes pinched off and released into extracellular space (74)(75)(76) potential-independent manner (71). Conversely, FGF-1 secretion is increased by cellular stresses such as heat shock (88), hypoxia (72), and serum starvation (73), while copper also can induce FGF-1 secretion by forming multiprotein aggregates in response to stress (89); however, FGF1 folding does not prevent its export (90).…”

Section: Galectinsmentioning

confidence: 99%

Immunological Significance of HMGB1 Post-Translational Modification and Redox Biology

et al. 2020

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Most extracellular proteins are secreted via the classical endoplasmic reticulum (ER)/Golgi-dependent secretion pathway; however, some proteins, including a few danger-associated molecular patterns (DAMPs), are secreted via non-classical ER/Golgi-independent secretion pathways. The evolutionarily conserved high mobility group box1 (HMGB1) is a ubiquitous nuclear protein that can be released by almost all cell types. HMGB1 lacks signal peptide and utilizes diverse non-canonical secretion mechanisms for its extracellular export. Although the post-translational modifications of HMGB1 were demonstrated, the oxidation of HMGB1 and secretion mechanisms are not highlighted yet. We currently investigated that peroxiredoxins I and II (PrxI/II) induce the intramolecular disulfide bond formation of HMGB1 in the nucleus. Disulfide HMGB1 is preferentially transported out of the nucleus by binding to the nuclear exportin chromosome-region maintenance 1 (CRM1). We determined the kinetics of HMGB1 oxidation in bone marrow-derived macrophage as early as a few minutes after lipopolysaccharide treatment, peaking at 4 h while disulfide HMGB1 accumulation was observed within the cells, starting to secrete in the late time point. We have shown that HMGB1 oxidation status, which is known to determine the biological activity in extracellular HMGB1, is crucial for the secretion of HMGB1 from the nucleus. This review summarizes selected aspects of HMGB1 redox biology relevant to the induction and propagation of inflammatory diseases. We implicate the immunological significance and the need for novel HMGB1 inhibitors through mechanism-based studies.

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Section: Galectinsmentioning

confidence: 99%

Immunological Significance of HMGB1 Post-Translational Modification and Redox Biology

et al. 2020

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“…Here we report that the mutation of proline 135 localized in this domain disturbed the folding of FGF1 and blocked its stress-induced secretion. We have demonstrated that aminopterin-dependent stable folding of the dihydrofolate reductase (DHFR) moiety in FGF1-DHFR chimera does not prevent its stress-induced release (20). These data and earlier results of experiments with FGF2-DHFR (19) indicate that nonclassical FGF secretion does not require protein unfolding.…”

Section: Discussionmentioning

confidence: 99%

Folding of Fibroblast Growth Factor 1 Is Critical for Its Nonclassical Release

et al. 2016

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Fibroblast growth factor 1 (FGF1), a ubiquitously expressed proangiogenic protein that is involved in tissue repair, carcinogenesis and maintenance of vasculature stability, is released from the cells via a stress-dependent nonclassical secretory pathway. FGF1 secretion is the result of transmembrane translocation of this protein. It correlates with FGF1 ability to permeabilize membranes composed of acidic phospholipids. Similarly to several other nonclassically exported proteins, FGF1 exhibits β-barrel folding. To assess the role of FGF1 folding in its secretion, we applied targeted mutagenesis in combination with a complex of biophysical methods and molecular dynamics studies, followed by artificial membrane permeabilization and stress-induced release experiments. It has been demonstrated that a mutation of proline 135 located in the C-terminus of FGF1 results in: (i) partial unfolding of FGF1, (ii) decrease of FGF1 ability to permeabilize bilayers composed of phosphatidylserine, and (iii) drastic inhibition of stress-induced FGF1 export. Thus, FGF1 folding is critical for its nonclassical secretion.

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“…[97] showed that disulfide bonded mutants of FGF1 having near-native like folding also can successfully translocate to cytosol. The experiments using chimeras with dihydrofolate reductase, which can be locked in folded conformation by its inhibitor aminopterin, demonstrated that neither FGF2 [98] nor FGF1 [38] require complete unfolding for their nonclassical release. Rajalingam et al ., [75] showed that a molten globule-like intermediate is structure realized in FGF1 under acidic conditions in the urea-induced unfolding pathway.…”

Section: Determining the Lipid Binding Domains Of Fgf1 Mrc Componentsmentioning

confidence: 99%

“…However, there exist also signal peptide-less proteins, which directly translocate through the cell membrane. Among them are FGF2, FGF1 and mature IL1α [10,37,38]. These proteins do not show a dot-like vesicular localization in the cytoplasm.…”

Section: Introductionmentioning

confidence: 99%

Protein-Phospholipid Interactions in Nonclassical Protein Secretion: Problem and Methods of Study

Prudovsky

Kumar

Sterling

et al. 2013

IJMS

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Extracellular proteins devoid of signal peptides use nonclassical secretion mechanisms for their export. These mechanisms are independent of the endoplasmic reticulum and Golgi. Some nonclassically released proteins, particularly fibroblast growth factors (FGF) 1 and 2, are exported as a result of their direct translocation through the cell membrane. This process requires specific interactions of released proteins with membrane phospholipids. In this review written by a cell biologist, a structural biologist and two membrane engineers, we discuss the following subjects: (i) Phenomenon of nonclassical protein release and its biological significance; (ii) Composition of the FGF1 multiprotein release complex (MRC); (iii) The relationship between FGF1 export and acidic phospholipid externalization; (iv) Interactions of FGF1 MRC components with acidic phospholipids; (v) Methods to study the transmembrane translocation of proteins; (vi) Membrane models to study nonclassical protein release.

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Protein folding does not prevent the nonclassical export of FGF1 and S100A13

Cited by 10 publications

References 53 publications

Immunological Significance of HMGB1 Post-Translational Modification and Redox Biology

Immunological Significance of HMGB1 Post-Translational Modification and Redox Biology

Folding of Fibroblast Growth Factor 1 Is Critical for Its Nonclassical Release

Protein-Phospholipid Interactions in Nonclassical Protein Secretion: Problem and Methods of Study

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