TG2 regulates the heat‐shock response by the post‐translational modification of HSF1

Rossin, Federica; Villella, Valeria Rachela; D’Eletto, Manuela; Farrace, Maria Grazia; Esposito, Speranza; Ferrari, Eleonora; Monzani, Romina; Occhigrossi, Luca; Pagliarini, Vittoria; Sette, Claudio; Cozza, Giorgio; Barlev, Nikolai A.; Falasca, Laura; Fimia, Gian María; Kroemer, Guido; Raia, Valeria; Maiuri, Luigi; Piacentini, Mauro

doi:10.15252/embr.201745067

Cited by 35 publications

(32 citation statements)

References 70 publications

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“…Among the drugs that inhibit TG2, there are two small molecules, cystamine and cysteamine. These two drugs are safe when administered in humans; cysteamine is used to treat cystinosis (33,34), and both cysteamine and cystamine have been used in human clinical trials in the treatment of diseases which directly or indirectly implicate TG2 and autophagy deregulation such as Huntington disease (35), cystic fibrosis (36,37), and celiac disease (38). It is noteworthy that cystamine has been used as a support treatment in cancer therapy (39).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Transglutaminase 2 as a Potential Host-Directed Therapy Against Mycobacterium tuberculosis

et al. 2020

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Host-directed therapies (HDTs) are emerging as a potential valid support in the treatment of drug-resistant tuberculosis (TB). Following our recent report indicating that genetic and pharmacological inhibition of transglutaminase 2 (TG2) restricts Mycobacterium tuberculosis (Mtb) replication in macrophages, we aimed to investigate the potentials of the TG2 inhibitors cystamine and cysteamine as HDTs against TB. We showed that both cysteamine and cystamine restricted Mtb replication in infected macrophages when provided at equimolar concentrations and did not exert any antibacterial activity when administered directly on Mtb cultures. Interestingly, infection of differentiated THP-1 mRFP-GFP-LC3B cells followed by the determination of the autophagic intermediates pH distribution (AIPD) showed that cystamine inhibited the autophagic flux while restricting Mtb replication. Moreover, both cystamine and cysteamine had a similar antimicrobial activity in primary macrophages infected with a panel of Mtb clinical strains belonging to different phylogeographic lineages. Evaluation of cysteamine and cystamine activity in the human ex vivo model of granuloma-like structures (GLS) further confirmed the ability of these drugs to restrict Mtb replication and to reduce the size of GLS. The antimicrobial activity of the TG2 inhibitors synergized with a second-line anti-TB drug as amikacin in human monocyte-derived macrophages and in the GLS model. Overall, the results of this study support the potential usefulness of the TG2-inhibitors cysteamine and cystamine as HDTs against TB.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Transglutaminase 2 as a Potential Host-Directed Therapy Against Mycobacterium tuberculosis

et al. 2020

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“…In order to obtain TG2 −/− mice carrying F508del‐CFTR mutation, C57BL/6 mice KO for TG2 (obtained from Gerry Melino, Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata”, Rome, Italy) were crossed with 129/FVB Cftr F508del/F508del mice (abbreviated Cftr F508del/F508del / TG2 −/− ), as described (Rossin et al , ). The newly generated mice were housed at Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata” (Rome, Italy).…”

Section: Methodsmentioning

confidence: 99%

A pathogenic role for cystic fibrosis transmembrane conductance regulator in celiac disease

Villella¹,

et al. 2018

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Intestinal handling of dietary proteins usually prevents local inflammatory and immune responses and promotes oral tolerance. However, in ~ 1% of the world population, gluten proteins from wheat and related cereals trigger an HLA DQ2/8‐restricted TH1 immune and antibody response leading to celiac disease. Prior epithelial stress and innate immune activation are essential for breaking oral tolerance to the gluten component gliadin. How gliadin subverts host intestinal mucosal defenses remains elusive. Here, we show that the α‐gliadin‐derived LGQQQPFPPQQPY peptide (P31–43) inhibits the function of cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel pivotal for epithelial adaptation to cell‐autonomous or environmental stress. P31–43 binds to, and reduces ATPase activity of, the nucleotide‐binding domain‐1 (NBD1) of CFTR, thus impairing CFTR function. This generates epithelial stress, tissue transglutaminase and inflammasome activation, NF‐κB nuclear translocation and IL‐15 production, that all can be prevented by potentiators of CFTR channel gating. The CFTR potentiator VX‐770 attenuates gliadin‐induced inflammation and promotes a tolerogenic response in gluten‐sensitive mice and cells from celiac patients. Our results unveil a primordial role for CFTR as a central hub orchestrating gliadin activities and identify a novel therapeutic option for celiac disease.

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“…At the apex synthetic drugs or natural compounds can be used to potentiate CFTR channel gating. Moreover, TGM2 inhibitors [12,15,18,19,29,57–59] or autophagy enhancers [60–64], can intercept the pro-inflammatory pathway downstream of CFTR malfunction.…”

Section: Discussionmentioning

confidence: 99%

Genistein antagonizes gliadin-induced CFTR malfunction in models of celiac disease

Esposito

Villella

Ferrari

et al. 2019

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In celiac disease (CD), an intolerance to dietary gluten/gliadin, antigenic gliadin peptides trigger an HLA-DQ2/DQ8-restricted adaptive Th1 immune response. Epithelial stress, induced by other non-antigenic gliadin peptides, is required for gliadin to become fully immunogenic. We found that cystic-fibrosis-transmembrane-conductance-regulator (CFTR) acts as membrane receptor for gliadin-derived peptide P31-43, as it binds to CFTR and impairs its channel function. P31-43-induced CFTR malfunction generates epithelial stress and intestinal inflammation. Maintaining CFTR in an active open conformation by the CFTR potentiators VX-770 (Ivacaftor) or Vrx-532, prevents P31-43 binding to CFTR and controls gliadin-induced manifestations. Here, we evaluated the possibility that the over-the-counter nutraceutical genistein, known to potentiate CFTR function, would allow to control gliadin-induced alterations. We demonstrated that pre-treatment with genistein prevented P31-43-induced CFTR malfunction and an epithelial stress response in Caco-2 cells. These effects were abrogated when the CFTR gene was knocked out by CRISP/Cas9 technology, indicating that genistein protects intestinal epithelial cells by potentiating CFTR function. Notably, genistein protected gliadin-sensitive mice from intestinal CFTR malfunction and gliadin-induced inflammation as it prevented gliadin-induced IFN-γ production by celiac peripheral-blood-mononuclear-cells (PBMC) cultured ex-vivo in the presence of P31-43-challenged Caco-2 cells. Our results indicate that natural compounds capable to increase CFTR channel gating might be used for the treatment of CD.

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TG2 regulates the heat‐shock response by the post‐translational modification of HSF1

Cited by 35 publications

References 70 publications

Inhibition of Transglutaminase 2 as a Potential Host-Directed Therapy Against Mycobacterium tuberculosis

Inhibition of Transglutaminase 2 as a Potential Host-Directed Therapy Against Mycobacterium tuberculosis

A pathogenic role for cystic fibrosis transmembrane conductance regulator in celiac disease

Genistein antagonizes gliadin-induced CFTR malfunction in models of celiac disease

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