Secretion of thioredoxin by normal and neoplastic cells through a leaderless secretory pathway.

Rubartelli, Anna; Bajetto, Adriana; Allavena, G; Wollman, Emmanuelle E.; Sitia, Roberto

doi:10.1016/s0021-9258(18)35742-9

Cited by 401 publications

(52 citation statements)

References 23 publications

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“…We labeled the surface of human T cells with biotin to determine if biotinylated PDI was released from the plasma membrane into the culture media, and/or was internalized into the cells. As shown in Figure 2A, we detected soluble biotinylated PDI in the culture medium between 24 h and 48 h after biotinylation, indicating that a fraction of cell surface PDI was shed from the cell surface, as has been shown for endothelial cells (Rubartelli et al 1992;Araujo et al 2017). Cell death did not appear to be involved in release of cell surface PDI, as we detected no increase in cell death over the time course of the experiment (data not shown).…”

Section: Release and Internalization Of Cell Surface Pdisupporting

confidence: 70%

“…The C-terminus of PDI contains a KDEL retention motif mechanism that retains PDI in the ER. However, while PDI reaches the plasma membrane via both classical and non-classical secretion pathways, little is known about how PDI is retained at the plasma membrane, or the specific events that trigger cell surface PDI localization (Rubartelli et al 1992;Yi and Khosla 2016;Araujo et al 2017). The KDEL sequence is present on cell surface PDI but is not required for plasma membrane retention (Yoshimori et al 1990;Terada et al 1995).…”

Section: Introductionmentioning

confidence: 99%

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Galectin-9 binds to O-glycans on protein disulfide isomerase

et al. 2017

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Changes in the T cell surface redox environment regulate critical cell functions, such as cell migration, viral entry and cytokine production. Cell surface protein disulfide isomerase (PDI) contributes to the regulation of T cell surface redox status. Cell surface PDI can be released into the extracellular milieu or can be internalized by T cells. We have found that galectin-9, a soluble lectin expressed by T cells, endothelial cells and dendritic cells, binds to and retains PDI on the cell surface. While endogenous galectin-9 is not required for basal cell surface PDI expression, exogenous galectin-9 mediated retention of cell surface PDI shifted the disulfide/thiol equilibrium on the T cell surface. O-glycans on PDI are required for galectin-9 binding, and PDI recognition appears to be specific for galectin-9, as galectin-1 and galectin-3 do not bind PDI. Galectin-9 is widely expressed by immune and endothelial cells in inflamed tissues, suggesting that T cells would be exposed to abundant galectin-9, in cis and in trans, in infectious or autoimmune conditions.

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Section: Release and Internalization Of Cell Surface Pdisupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Galectin-9 binds to O-glycans on protein disulfide isomerase

et al. 2017

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“…Besides its two active site cysteinyl residues, cytosolic Trx1 possesses three additional structural cysteinyl residues that were implicated in regulatory function and Trx1-dimer formation [15,16]. Trx1 does not contain a nuclear localization signal nor a signal peptide for secretion, but it was observed to translocate into the nucleus under certain conditions and also to be secreted in a nonclassic way, independent of its redox state [17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Molecular Basis for the Interactions of Human Thioredoxins with Their Respective Reductases

Hossain

Bodnar

Klein

et al. 2021

Oxidative Medicine and Cellular Longevity

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The mammalian cytosolic thioredoxin (Trx) system consists of Trx1 and its reductase, the NADPH-dependent seleno-enzyme TrxR1. These proteins function as electron donor for metabolic enzymes, for instance in DNA synthesis, and the redox regulation of numerous processes. In this work, we analysed the interactions between these two proteins. We proposed electrostatic complementarity as major force controlling the formation of encounter complexes between the proteins and thus the efficiency of the subsequent electron transfer reaction. If our hypothesis is valid, formation of the encounter complex should be independent of the redox reaction. In fact, we were able to confirm that also a redox inactive mutant of Trx1 lacking both active site cysteinyl residues (C32,35S) binds to TrxR1 in a similar manner and with similar kinetics as the wild-type protein. We have generated a number of mutants with alterations in electrostatic properties and characterised their interaction with TrxR1 in kinetic assays. For human Trx1 and TrxR1, complementary electrostatic surfaces within the area covered in the encounter complex appear to control the affinity of the reductase for its substrate Trx. Electrostatic compatibility was even observed in areas that do not form direct molecular interactions in the encounter complex, and our results suggest that the electrostatic complementarity in these areas influences the catalytic efficiency of the reduction. The human genome encodes ten cytosolic Trx-like or Trx domain-containing proteins. In agreement with our hypothesis, the proteins that have been characterised as TrxR1 substrates also show the highest similarity in their electrostatic properties.

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“…The function of TXN in vivo remains unclear. Txn1 is located in the cytoplasm, nucleus, and extracellular region [25,28], whereas Txn2 is located in the mitochondria [29]. A homozygous TXN2 mutation has been linked to an infantile-onset neurodegenerative disorder with severe cerebellar and optic atrophy and peripheral neuropathy [30].…”

Section: Discussionmentioning

confidence: 99%

Txn1 mutation causes epilepsy associated with vacuolar degeneration in the midbrain

Ohmori

Ouchida

Imai

et al. 2021

Preprint

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Thioredoxin (TXN), encoded by Txn1, acts as a critical antioxidant in the defense against oxidative stress by regulating the dithiol/disulfide balance of interacting proteins. The role of TXN in the central nervous system (CNS) is largely unknown. A phenotype-driven study of N-ethyl-N-nitrosourea-mutated rats with running seizures at around five-week of age revealed the relevance of Txn1 mutations to CNS disorders. Genetic mapping identified Txn1-F54L in epileptic rats. The insulin-reducing activity of Txn1-F54L rats was approximately one-third that of the wild-type. Vacuolar degeneration in the midbrain, mainly in the thalamus and the inferior colliculus, was observed in the Txn1-F54L rats. The lesions displayed neuronal and oligodendrocyte cell death. Neurons in Txn1-F54L rats showed morphological changes in the mitochondria. Vacuolar degeneration began at three weeks of age, and spontaneous repair began at seven weeks; a dramatic change from cell death to repair occurred in the midbrain during a restricted period. In conclusion, Txn1 is essential for the development of the midbrain in juvenile rats.

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Secretion of thioredoxin by normal and neoplastic cells through a leaderless secretory pathway.

Cited by 401 publications

References 23 publications

Galectin-9 binds to O-glycans on protein disulfide isomerase

Galectin-9 binds to O-glycans on protein disulfide isomerase

Molecular Basis for the Interactions of Human Thioredoxins with Their Respective Reductases

Txn1 mutation causes epilepsy associated with vacuolar degeneration in the midbrain

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