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Short-term TNFα shedding is independent of cytoplasmic phosphorylation or furin cleavage of ADAM17

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Short-term TNFα shedding is independent of cytoplasmic phosphorylation or furin cleavage of ADAM17. / Schwarz, Jeanette; Broder, Claudia; Helmstetter, Ansgard; Schmidt, Stefanie; Yan, Isabell; Müller, Miryam; Schmidt-Arras, Dirk; Becker-Pauly, Christoph; Nolte, Friedrich; Mittrücker, Hans-Willi; Rabe, Björn; Rose-John, Stefan; Chalaris, Athena.

In: BBA-MOL CELL RES, Vol. 1833, No. 12, 01.12.2013, p. 3355-67.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Schwarz, J, Broder, C, Helmstetter, A, Schmidt, S, Yan, I, Müller, M, Schmidt-Arras, D, Becker-Pauly, C, Nolte, F, Mittrücker, H-W, Rabe, B, Rose-John, S & Chalaris, A 2013, 'Short-term TNFα shedding is independent of cytoplasmic phosphorylation or furin cleavage of ADAM17', BBA-MOL CELL RES, vol. 1833, no. 12, pp. 3355-67. https://doi.org/10.1016/j.bbamcr.2013.10.005

APA

Schwarz, J., Broder, C., Helmstetter, A., Schmidt, S., Yan, I., Müller, M., Schmidt-Arras, D., Becker-Pauly, C., Nolte, F., Mittrücker, H-W., Rabe, B., Rose-John, S., & Chalaris, A. (2013). Short-term TNFα shedding is independent of cytoplasmic phosphorylation or furin cleavage of ADAM17. BBA-MOL CELL RES, 1833(12), 3355-67. https://doi.org/10.1016/j.bbamcr.2013.10.005

Vancouver

Schwarz J, Broder C, Helmstetter A, Schmidt S, Yan I, Müller M et al. Short-term TNFα shedding is independent of cytoplasmic phosphorylation or furin cleavage of ADAM17. BBA-MOL CELL RES. 2013 Dec 1;1833(12):3355-67. https://doi.org/10.1016/j.bbamcr.2013.10.005

Bibtex

@article{a8a04565b1604690a0cc57a39b7d210e,
title = "Short-term TNFα shedding is independent of cytoplasmic phosphorylation or furin cleavage of ADAM17",
abstract = "Proteolysis of transmembrane molecules is an irreversible post-translational modification enabling autocrine, paracrine and endocrine signaling of many cytokines. The pro-inflammatory activities of membrane bound TNFα (pro-TNFα) strongly depend on ectodomain shedding mediated by the A Disintegrin And Metalloprotease family member ADAM17. Despite the well-documented role of ADAM17 in pro-TNFα cleavage during inflammation, little is known about its regulation. Mitogen-activated protein kinase-induced phosphorylation of the ADAM17 cytoplasmic tail has been described to be required for proper activation. To address, if pro-TNFα shedding depends on cytosolic phosphorylation we analyzed ADAM17 mutants lacking the cytoplasmic domain. ADAM17 mediated shedding of pro-TNFα was induced by PMA, Anisomycin and the phosphatase inhibitors Cantharidin and Calyculin A. Deletion of the entire cytoplasmic portion of ADAM17 abolished furin-dependent proteolytic maturation and pro-TNFα cleavage. Interestingly, we could exclude that resistance to proconvertase processing is the reason for the enzymatic inactivity of ADAM17 lacking the cytoplasmic portion as furin-resistant ADAM17 mutants rescued genetic ADAM17 deficiency after mitogen-activated protein kinase activation. Adding only 6 cytoplasmic amino acids completely restored ADAM17 maturation and shedding of pro-TNFα as well as of both TNF-receptors Finally, we showed that a pro-TNFα mutant lacking the cytoplasmic portion was also shed from the cell surface. We conclude that pro-TNFα cleavage by its major sheddase ADAM17 does not depend on cytosolic phosphorylation and/or interaction. These results have general implications on understanding the activation mechanism controlling the activity of ADAM17.",
keywords = "ADAM Proteins, Animals, Cell Line, Cytoplasm, Furin, Humans, Mice, Mutant Proteins, Phosphorylation, Protein Multimerization, Protein Processing, Post-Translational, Protein Structure, Tertiary, Protein Transport, Proteolysis, Tumor Necrosis Factor-alpha",
author = "Jeanette Schwarz and Claudia Broder and Ansgard Helmstetter and Stefanie Schmidt and Isabell Yan and Miryam M{\"u}ller and Dirk Schmidt-Arras and Christoph Becker-Pauly and Friedrich Nolte and Hans-Willi Mittr{\"u}cker and Bj{\"o}rn Rabe and Stefan Rose-John and Athena Chalaris",
note = "{\textcopyright} 2013.",
year = "2013",
month = dec,
day = "1",
doi = "10.1016/j.bbamcr.2013.10.005",
language = "English",
volume = "1833",
pages = "3355--67",
journal = "BBA-MOL CELL RES",
issn = "0167-4889",
publisher = "Elsevier",
number = "12",

}

RIS

TY - JOUR

T1 - Short-term TNFα shedding is independent of cytoplasmic phosphorylation or furin cleavage of ADAM17

AU - Schwarz, Jeanette

AU - Broder, Claudia

AU - Helmstetter, Ansgard

AU - Schmidt, Stefanie

AU - Yan, Isabell

AU - Müller, Miryam

AU - Schmidt-Arras, Dirk

AU - Becker-Pauly, Christoph

AU - Nolte, Friedrich

AU - Mittrücker, Hans-Willi

AU - Rabe, Björn

AU - Rose-John, Stefan

AU - Chalaris, Athena

N1 - © 2013.

PY - 2013/12/1

Y1 - 2013/12/1

N2 - Proteolysis of transmembrane molecules is an irreversible post-translational modification enabling autocrine, paracrine and endocrine signaling of many cytokines. The pro-inflammatory activities of membrane bound TNFα (pro-TNFα) strongly depend on ectodomain shedding mediated by the A Disintegrin And Metalloprotease family member ADAM17. Despite the well-documented role of ADAM17 in pro-TNFα cleavage during inflammation, little is known about its regulation. Mitogen-activated protein kinase-induced phosphorylation of the ADAM17 cytoplasmic tail has been described to be required for proper activation. To address, if pro-TNFα shedding depends on cytosolic phosphorylation we analyzed ADAM17 mutants lacking the cytoplasmic domain. ADAM17 mediated shedding of pro-TNFα was induced by PMA, Anisomycin and the phosphatase inhibitors Cantharidin and Calyculin A. Deletion of the entire cytoplasmic portion of ADAM17 abolished furin-dependent proteolytic maturation and pro-TNFα cleavage. Interestingly, we could exclude that resistance to proconvertase processing is the reason for the enzymatic inactivity of ADAM17 lacking the cytoplasmic portion as furin-resistant ADAM17 mutants rescued genetic ADAM17 deficiency after mitogen-activated protein kinase activation. Adding only 6 cytoplasmic amino acids completely restored ADAM17 maturation and shedding of pro-TNFα as well as of both TNF-receptors Finally, we showed that a pro-TNFα mutant lacking the cytoplasmic portion was also shed from the cell surface. We conclude that pro-TNFα cleavage by its major sheddase ADAM17 does not depend on cytosolic phosphorylation and/or interaction. These results have general implications on understanding the activation mechanism controlling the activity of ADAM17.

AB - Proteolysis of transmembrane molecules is an irreversible post-translational modification enabling autocrine, paracrine and endocrine signaling of many cytokines. The pro-inflammatory activities of membrane bound TNFα (pro-TNFα) strongly depend on ectodomain shedding mediated by the A Disintegrin And Metalloprotease family member ADAM17. Despite the well-documented role of ADAM17 in pro-TNFα cleavage during inflammation, little is known about its regulation. Mitogen-activated protein kinase-induced phosphorylation of the ADAM17 cytoplasmic tail has been described to be required for proper activation. To address, if pro-TNFα shedding depends on cytosolic phosphorylation we analyzed ADAM17 mutants lacking the cytoplasmic domain. ADAM17 mediated shedding of pro-TNFα was induced by PMA, Anisomycin and the phosphatase inhibitors Cantharidin and Calyculin A. Deletion of the entire cytoplasmic portion of ADAM17 abolished furin-dependent proteolytic maturation and pro-TNFα cleavage. Interestingly, we could exclude that resistance to proconvertase processing is the reason for the enzymatic inactivity of ADAM17 lacking the cytoplasmic portion as furin-resistant ADAM17 mutants rescued genetic ADAM17 deficiency after mitogen-activated protein kinase activation. Adding only 6 cytoplasmic amino acids completely restored ADAM17 maturation and shedding of pro-TNFα as well as of both TNF-receptors Finally, we showed that a pro-TNFα mutant lacking the cytoplasmic portion was also shed from the cell surface. We conclude that pro-TNFα cleavage by its major sheddase ADAM17 does not depend on cytosolic phosphorylation and/or interaction. These results have general implications on understanding the activation mechanism controlling the activity of ADAM17.

KW - ADAM Proteins

KW - Animals

KW - Cell Line

KW - Cytoplasm

KW - Furin

KW - Humans

KW - Mice

KW - Mutant Proteins

KW - Phosphorylation

KW - Protein Multimerization

KW - Protein Processing, Post-Translational

KW - Protein Structure, Tertiary

KW - Protein Transport

KW - Proteolysis

KW - Tumor Necrosis Factor-alpha

U2 - 10.1016/j.bbamcr.2013.10.005

DO - 10.1016/j.bbamcr.2013.10.005

M3 - SCORING: Journal article

C2 - 24135057

VL - 1833

SP - 3355

EP - 3367

JO - BBA-MOL CELL RES

JF - BBA-MOL CELL RES

SN - 0167-4889

IS - 12

ER -