Unconventional Secretion, Gate to Homeoprotein Intercellular Transfer

Joliot, Alain; Prochiantz, Alain

doi:10.3389/fcell.2022.926421

Cited by 6 publications

(6 citation statements)

References 68 publications

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“…In conclusion, with the current study, important insights were obtained regarding the highly dynamic process of PI(4,5)P2-dependent FGF2 oligomerization on membrane surfaces, the key trigger of the central step in the unconventional secretion of FGF2 from cells, the remodeling of the plasma membrane lipid bilayer into a lipidic membrane pore with a toroidal architecture. With a number of other cargo proteins secreted by UPS type I pathways in a PI(4,5)P2-dependent manner such as HIV-Tat, Tau and homeoproteins (Rayne et al, 2010;Debaisieux et al, 2012;Rabouille, 2017;Katsinelos et al, 2018;Merezhko et al, 2018;Merezhko, Uronen and Huttunen, 2020;Joliot and Prochiantz, 2022;Sparn et al, 2022b), our findings pave the way for a deeper understanding of the general principles of UPS type I pathways of unconventional protein secretion.…”

Section: Discussionmentioning

confidence: 79%

“…With regard to soluble cytoplasmic proteins lacking N-terminal signal peptides, two principal pathways have been identified. One of them is characterized by direct protein translocation across the plasma membrane, a process termed UPS Type I with FGF2 (Sparn et al, 2022b), HIV-Tat (Rayne et al, 2010; Schatz, Tong and Beaumelle, 2018), Tau (Katsinelos et al, 2018; Merezhko et al, 2018; Katsinelos et al, 2021) and homeoproteins (Amblard et al, 2020; Joliot and Prochiantz, 2022) being examples. A second pathway mediating unconventional secretion of soluble cytoplasmic cargo proteins known as UPS Type III is based on intracellular vesicle intermediates such as autophagosomes or endocytic compartments (Malhotra, 2013; Zhang and Schekman, 2013; Rabouille, 2017; Dimou and Nickel, 2018; Ye, 2018; Liu, Zhang and Ge, 2020).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Disulfide bridge-dependent dimerization triggers FGF2 membrane translocation into the extracellular space

Lolicato

Steringer

Saleppico

et al. 2023

Preprint

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Fibroblast Growth Factor 2 (FGF2) exits cells by direct translocation across the plasma membrane, a type I pathway of unconventional protein secretion. This process is initiated by PI(4,5)P2-dependent formation of highly dynamic FGF2 oligomers at the inner plasma membrane leaflet, inducing the formation of lipidic membrane pores. Cell surface heparan sulfate chains linked to glypican-1 (GPC1) capture FGF2 at the outer plasma membrane leaflet, completing FGF2 membrane translocation into the extracellular space. While the basic steps of this pathway are well understood, the molecular mechanism by which FGF2 oligomerizes on membrane surfaces remains unclear. In the current study, we show FGF2 dimerization on membrane surfaces to be dependent on the formation of a C95-C95 disulfide bridge, producing the building block for higher FGF2 oligomers that drive the formation of membrane pores. We find FGF2 with a C95A substitution to be defective in oligomerization, pore formation, and membrane translocation. Consistently, we demonstrate a C95A variant of FGF2 to be characterized by a severe secretion phenotype. By contrast, while also important for efficient FGF2 secretion from cells, a second cysteine residue on the molecular surface of FGF2 (C77) is not involved in FGF2 oligomerization. Rather, we find C77 to be part of the protein-protein interaction interface through which FGF2 binds to the alpha 1 subunit of the Na,K-ATPase, the landing platform for FGF2 at the inner plasma membrane leaflet. Using atomistic molecular dynamics simulations and cryo-electron tomography, we provide insights into the protein-protein interface of C95-C95 disulfide bridged FGF2 dimers and propose a mechanism by which they bind with high avidity to PI(4,5)P2 on membrane surfaces. Our findings further imply a tight coupling between FGF2 secretion and the formation of ternary signaling complexes on cell surfaces, indicating that C95-C95 bridged FGF2 dimers are functioning as the molecular units triggering autocrine and paracrine FGF2 signaling.

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Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Disulfide bridge-dependent dimerization triggers FGF2 membrane translocation into the extracellular space

Lolicato

Steringer

Saleppico

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…With regard to soluble cytoplasmic proteins lacking N-terminal signal peptides, two principal pathways have been identified. One of them is characterized by direct protein translocation across the plasma membrane, a process termed UPS type I with FGF2 ( Sparn et al, 2022b ), HIV-Tat ( Rayne et al, 2010 ; Schatz et al, 2018 ), Tau ( Katsinelos et al, 2018 ; Merezhko et al, 2018 ; Katsinelos et al, 2021 ), and homeoproteins ( Amblard et al, 2020 ; Joliot and Prochiantz, 2022 ) being examples. A second pathway mediating unconventional secretion of soluble cytoplasmic cargo proteins known as UPS type III is based on intracellular vesicle intermediates such as autophagosomes or endocytic compartments ( Malhotra, 2013 ; Zhang and Schekman, 2013 ; Rabouille, 2017 ; Dimou and Nickel, 2018 ; Ye, 2018 ; Liu et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Disulfide bridge-dependent dimerization triggers FGF2 membrane translocation into the extracellular space

Lolicato

Steringer

Saleppico

et al. 2024

eLife

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Fibroblast Growth Factor 2 (FGF2) exits cells by direct translocation across the plasma membrane, a type I pathway of unconventional protein secretion. This process is initiated by PI(4,5)P2-dependent formation of highly dynamic FGF2 oligomers at the inner plasma membrane leaflet, inducing the formation of lipidic membrane pores. Cell surface heparan sulfate chains linked to glypican-1 (GPC1) capture FGF2 at the outer plasma membrane leaflet, completing FGF2 membrane translocation into the extracellular space. While the basic steps of this pathway are well understood, the molecular mechanism by which FGF2 oligomerizes on membrane surfaces remains unclear. In the current study, we show FGF2 dimerization on membrane surfaces to be dependent on the formation of a C95-C95 disulfide bridge, producing the building block for higher FGF2 oligomers that drive the formation of membrane pores. We find FGF2 with a C95A substitution to be defective in oligomerization, pore formation, and membrane translocation. Consistently, we demonstrate a C95A variant of FGF2 to be characterized by a severe secretion phenotype. By contrast, while also important for efficient FGF2 secretion from cells, a second cysteine residue on the molecular surface of FGF2 (C77) is not involved in FGF2 oligomerization. Rather, we find C77 to be part of the protein-protein interaction interface through which FGF2 binds to the α1 subunit of the Na,K-ATPase, the landing platform for FGF2 at the inner plasma membrane leaflet. Using atomistic molecular dynamics simulations and cryo-electron tomography, we provide insights into the protein-protein interface of C95-C95 disulfide bridged FGF2 dimers and propose a mechanism by which they bind with high avidity to PI(4,5)P2 on membrane surfaces. Our findings further imply a tight coupling between FGF2 secretion and the formation of ternary signaling complexes on cell surfaces, indicating that C95-C95 bridged FGF2 dimers are functioning as the molecular units triggering autocrine and paracrine FGF2 signaling.

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“…The unexpected, and thus unconventional protein secretion (UPS), was later recognized to operate by four different processes [ 10 ]. Types 1 and 2 of UPS [ 11 , 12 ], typical of fluid proteins, were thought to depend on distinct agents of the plasma membrane including diffusion through lipids and binding/transport of molecules by surface channels and transporters [ 11 – 13 ]. The members of these two fluid types are numerous.…”

Section: Introductionmentioning

confidence: 99%

Unconventional protein secretion (UPS): role in important diseases

Meldolesi

2023

Mol Biomed

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Unconventional protein secretion (UPS) is the new secretion process discovered in liquid form over three decades ago. More recently, UPS has been shown to operate also in solid forms generated from four types of organelles: fractions of lysosomes and autophagy (APh) undergoing exocytosis; exosomes and ectosomes, with their extracellular vesicles (EVs). Recently many mechanisms and proteins of these solid forms have been shown to depend on UPS. An additional function of UPS is the regulation of diseases, often investigated separately from each other. In the present review, upon short presentation of UPS in healthy cells and organs, interest is focused on the mechanisms and development of diseases. The first reported are neurodegenerations, characterized by distinct properties. Additional diseases, including inflammasomes, inflammatory responses, glial effects and other diseases of various origin, are governed by proteins generated, directly or alternatively, by UPS. The diseases most intensely affected by UPS are various types of cancer, activated in most important processes: growth, proliferation and invasion, relapse, metastatic colonization, vascular leakiness, immunomodulation, chemoresistence. The therapy role of UPS diseases depends largely on exosomes. In addition to affecting neurodegenerative diseases, its special aim is the increased protection against cancer. Its immense relevance is due to intrinsic features, including low immunogenicity, biocompatibility, stability, and crossing of biological barriers. Exosomes, loaded with factors for pharmacological actions and target cell sensitivity, induce protection against various specific cancers. Further expansion of disease therapies is expected in the near future.

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Unconventional Secretion, Gate to Homeoprotein Intercellular Transfer

Cited by 6 publications

References 68 publications

Disulfide bridge-dependent dimerization triggers FGF2 membrane translocation into the extracellular space

Disulfide bridge-dependent dimerization triggers FGF2 membrane translocation into the extracellular space

Disulfide bridge-dependent dimerization triggers FGF2 membrane translocation into the extracellular space

Unconventional protein secretion (UPS): role in important diseases

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