Control of TG Functions Depending on Their Localization

Furutani, Yutaka; Kojima, Soichi

doi:10.1007/978-4-431-55825-5_2

Cited by 4 publications

(5 citation statements)

References 101 publications

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“…Transglutaminases (TGs) are enzymes that catalyze proteinprotein covalent cross-linking between Lys and Gln residues to form ⑀-(␥-glutamyl)lysine bonds and promote blood/hemolymph coagulation and skin/cuticle formation, and control signal transduction (13)(14)(15). TGs are present intracellularly and extracellularly, and their substrates are ubiquitously distributed in metazoans (16,17). Soluble secretory proteins with the N-terminal signal sequence for secretion are secreted into the extracellular space through the conventional ER/Golgi-dependent secretory pathway (18).…”

mentioning

confidence: 99%

Drosophila TG-A transglutaminase is secreted via an unconventional Golgi-independent mechanism involving exosomes and two types of fatty acylations

Shibata¹,

Hadano²,

Kawasaki³

et al. 2017

Journal of Biological Chemistry

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Transglutaminases (TGs) play essential intracellular and extracellular roles by covalently cross-linking many proteins. TG is encoded by one gene and has two alternative splicing-derived isoforms, TG-A and TG-B, which contain distinct N-terminal 46- and 38-amino acid sequences, respectively. The TGs identified to date do not have a typical endoplasmic reticulum (ER)-signal peptide, and the molecular mechanisms of their secretion under physiologic conditions are unclear. Immunocytochemistry revealed that TG-A localizes to multivesicular-like structures, whereas TG-B localizes to the cytosol. We also found that TG-A, but not TG-B, was modified concomitantly bymyristoylation and -palmitoylation, andmyristoylation was a pre-requisite for palmitoylation. Moreover, TG-A, but not TG-B, was secreted in response to calcium signaling induced by Ca ionophores and uracil, a pathogenic bacteria-derived substance. Brefeldin A and monensin, inhibitors of the ER/Golgi-mediated conventional pathway, did not suppress TG-A secretion, whereas inhibition of -palmitoylation by 2-bromopalmitate blocked TG-A secretion. Ultracentrifugation, electron microscopy analyses, and treatments with inhibitors of multivesicular body formation revealed that TG-A was secreted via exosomes together with co-transfected mammalian CD63, an exosomal marker, and the secreted TG-A was taken up by other cells. The 8-residue N-terminal fragment of TG-A containing the fatty acylation sites was both necessary and sufficient for the exosome-dependent secretion of TG-A. In conclusion, TG-A is secreted through an unconventional ER/Golgi-independent pathway involving two types of fatty acylations and exosomes.

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mentioning

confidence: 99%

Drosophila TG-A transglutaminase is secreted via an unconventional Golgi-independent mechanism involving exosomes and two types of fatty acylations

Shibata¹,

Hadano²,

Kawasaki³

et al. 2017

Journal of Biological Chemistry

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“…Although the biological role of MTG in the host organism is unclear, 9 the obtained results imply that the action of TGase with regard to macromolecular substrates may be intrinsically enhanced in a crowded environment, facilitating the formation of biologically important crosslinked products in nature. 37…”

Section: Resultsmentioning

confidence: 99%

Molecular crowding elicits the acceleration of enzymatic crosslinking of macromolecular substrates

et al. 2023

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“…CTSL and TGM3 co‐localize in hair follicles [122], and the phenotype of TGM3 ‐deficient patients is restricted to hair defects (Table 1). Furthermore, TGM5 crosslinks loricrin, involucrin, and SPRs [119] and endogenous protease inhibitors, since patients with acral peeling skin syndrome (APSS) caused by inactivating mutations in TGM5 (Table 1) display increased proteolytic activities [5]. The mechanism of TGM5 activation is unclear [119], but cystatin M/E (CST6), present mainly in hair follicles [123], inhibits CTSL, the activator of TGMs [121].…”

Section: Transglutaminases As New Regulators Of Epidermal Proteolysismentioning

confidence: 99%

“…Cathepsin D (CTSD) produces active TGM1 from the zymogen in vivo, and Ctsd À/À mice display accumulation of proTGM1 [118]. TGM1 is responsible for crosslinking involucrin, loricrin, and small proline-rich protein (SPR) 1 and 2, and the protease inhibitors SKALP/elafin and SPINK6 [119,120]. On the other hand, CTSL activates CTSD and TGM3 [121], which is responsible for crosslinking SPINK6 to the extracellular microenvironment [119].…”

Section: Transglutaminases As New Regulators Of Epidermal Proteolysismentioning

confidence: 99%

“…TGM1 is responsible for crosslinking involucrin, loricrin, and small proline-rich protein (SPR) 1 and 2, and the protease inhibitors SKALP/elafin and SPINK6 [119,120]. On the other hand, CTSL activates CTSD and TGM3 [121], which is responsible for crosslinking SPINK6 to the extracellular microenvironment [119]. Since the level of SPINK6 is higher in palms and feet relative to other skin areas [112], that TGM1 mutations cause autosomal recessive congenital ichthyosis (ARCI) with palmoplantar fissures (Table 1) is consistent with the lack of SPINK6 crosslinking at these sites.…”

Section: Transglutaminases As New Regulators Of Epidermal Proteolysismentioning

confidence: 99%

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Reconstructing the epidermal proteolytic cascades in health and disease

Sotiropoulou

Zingkou

Pampalakis

2022

The Journal of Pathology

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The epidermis is the outer stratified epithelium of the skin, forming the physical barrier that is indispensable for homeostasis. Epidermal proteolysis, mainly but not exclusively executed by kallikrein-related peptidases (KLKs), is tightly regulated to ensure maintenance of physiological skin renewal and an intact skin barrier. Perturbation of epidermal proteolytic networks is implicated in a wide array of rare and common skin pathologies of diverse genetic backgrounds. Recent studies of monogenic human skin diseases and newly developed animal models have revealed new mechanisms of regulation of proteolytic pathways in epidermal physiology and in disease states. These new data have challenged some accepted views, for example the role of matriptase in epidermal desquamation, which turned out to be restricted to mouse skin. The significance of PAR2 signaling in skin inflammation should also be reconsidered in the face of recent findings. Cumulatively, recent studies necessitate a sophisticated redefinition of the proteolytic and signaling pathways that operate in human skin. We elaborate how epidermal proteolysis is finely regulated at multiple levels, and in a spatial manner that has not been taken into consideration so far, in which specific proteases are confined to distinct epidermal sublayers. Of interest, transglutaminases have emerged as regulators of epidermal proteolysis and desquamation by spatially fixing endogenous protease inhibitors, constituting regulatory factors that were not recognized before. Furthermore, new evidence suggests a link between proteolysis and lipid metabolism. By synthesis of established notions and recent discoveries, we provide an up-to-date critical evaluation and synthesis of current knowledge and the extended complexity of proteolysis regulation and signaling pathways in skin.

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Control of TG Functions Depending on Their Localization

Cited by 4 publications

References 101 publications

Drosophila TG-A transglutaminase is secreted via an unconventional Golgi-independent mechanism involving exosomes and two types of fatty acylations

Drosophila TG-A transglutaminase is secreted via an unconventional Golgi-independent mechanism involving exosomes and two types of fatty acylations

Molecular crowding elicits the acceleration of enzymatic crosslinking of macromolecular substrates

Reconstructing the epidermal proteolytic cascades in health and disease

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