Regulation of Immunoproteasome Function in the Lung

Keller, Ilona; Vosyka, Oliver; Takenaka, Shinji; Kloß, Alexander; Dahlmann, Burkhardt; Willems, Lianne I.; Verdoes, Martijn; Overkleeft, Hermen S.; Marcos, Élisabeth; Adnot, Serge; Hauck, Stefanie M.; Ruppert, Clemens; Günther, Andreas; Herold, Susanne; Ohno, Shinji; Adler, Heiko; Eickelberg, Oliver; Meiners, Silke

doi:10.1038/srep10230

Cited by 54 publications

(54 citation statements)

References 53 publications

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“…Recently, up-regulated expression of immunoproteasome subunits in solid tumors has been reported, with preserved basal level in normal epithelium. This finding is notable because the immunoproteasome was previously thought to be constitutively expressed only in dendritic cells, macrophages, or activated lymphocytes (20,21). We observed substantial heterogeneity in mRNA and protein expression of immunoproteasome-related genes among NSCLC cell lines.…”

Section: Discussionmentioning

confidence: 61%

Immunoproteasome deficiency is a feature of non-small cell lung cancer with a mesenchymal phenotype and is associated with a poor outcome

Tripathi

Peters

Taguchi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

180

175

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The immunoproteasome plays a key role in generation of HLA peptides for T cell-mediated immunity. Integrative genomic and proteomic analysis of non-small cell lung carcinoma (NSCLC) cell lines revealed significantly reduced expression of immunoproteasome components and their regulators associated with epithelial to mesenchymal transition. Low expression of immunoproteasome subunits in early stage NSCLC patients was associated with recurrence and metastasis. Depleted repertoire of HLA class I-bound peptides in mesenchymal cells deficient in immunoproteasome components was restored with either IFNγ or 5-aza-2′-deoxycytidine (5-aza-dC) treatment. Our findings point to a mechanism of immune evasion of cells with a mesenchymal phenotype and suggest a strategy to overcome immune evasion through induction of the immunoproteasome to increase the cellular repertoire of HLA class I-bound peptides.

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Section: Discussionmentioning

confidence: 61%

Immunoproteasome deficiency is a feature of non-small cell lung cancer with a mesenchymal phenotype and is associated with a poor outcome

Tripathi

Peters

Taguchi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

180

175

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“…Western Blotting Analysis-Cells were lysed in TSDG or RIPA buffer as previously reported (40 Gel Filtration Assay-HeLa cells grown in DMEM (Lonza) containing 4.5 g/liter of glucose, 10% heat inactivated fetal bovine serum (Biowest), 2 mM glutamine, 100 units/ml of penicillin, and 10 mg/ml of streptomycin (Lonza), treated or not with 10 nM bortezomib for 24 h, were harvested, washed with PBS, and kept frozen at Ϫ80°C. Cells were lysed for 10 min at 4°C in 50 mM Tris/HCl (pH 8.0), 0.5% Igepal CA-630, 5 mM MgCl 2 , 0.5 mM EDTA, 10% (v/v) glycerol, 50 mM NaCl, 1 mM ATP, 1 mM DTT.…”

Section: Methodsmentioning

confidence: 99%

“…Quantitative Real-time RT-PCR-RNA extraction was from phLF using the Roti-Quick-Kit (Carl Roth), reverse transcription and quantitative PCR was performed as previously described (40). The 60S ribosomal protein L19 (RPL19) served as a housekeeping gene for relative expression analysis.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Proteasome Activity Induces Formation of Alternative Proteasome Complexes

Welk

Coux

Kleene

et al. 2016

Journal of Biological Chemistry

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The proteasome is an intracellular protease complex consisting of the 20S catalytic core and its associated regulators, including the 19S complex, PA28␣␤, PA28␥, PA200, and PI31. Inhibition of the proteasome induces autoregulatory de novo formation of 20S and 26S proteasome complexes. Formation of alternative proteasome complexes, however, has not been investigated so far. We here show that catalytic proteasome inhibition results in fast recruitment of PA28␥ and PA200 to 20S and 26S proteasomes within 2-6 h. Rapid formation of alternative proteasome complexes did not involve transcriptional activation of PA28␥ and PA200 but rather recruitment of preexisting activators to 20S and 26S proteasome complexes. Recruitment of proteasomal activators depended on the extent of active site inhibition of the proteasome with inhibition of ␤5 active sites being sufficient for inducing recruitment. Moreover, specific inhibition of 26S proteasome activity via siRNA-mediated knockdown of the 19S subunit RPN6 induced recruitment of only PA200 to 20S proteasomes, whereas PA28␥ was not mobilized. Here, formation of alternative PA200 complexes involved transcriptional activation of the activator. Alternative proteasome complexes persisted when cells had regained proteasome activity after pulse exposure to proteasome inhibitors. Knockdown of PA28␥ sensitized cells to proteasome inhibitor-mediated growth arrest. Thus, formation of alternative proteasome complexes appears to be a formerly unrecognized but integral part of the cellular response to impaired proteasome function and altered proteostasis.The proteasome, one of the main proteolytic systems of the cell, is essential for maintenance of protein homeostasis and thus of cellular functions. The proteolytic activity of this multicatalytic protease resides inside the 20S core particle, built of four stacked rings of seven ␣ and ␤ subunits with ␣ 7

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“…La inducción rápida y específica de inmunoproteasomas es necesaria para la eliminación eficaz de las células infectadas. 71,72 Los pacientes con EPOC sufren más infecciones respiratorias y necesitan más tiempo para resolverlas. El humo del cigarro altera el sistema inmune en respuesta a infecciones, favoreciendo las exacerba- …”

Section: 63unclassified

Inmunopatología de la enfermedad pulmonar obstructiva crónica

Martínez-Aguilar

Vargas-Camaño

Hernandez-Pliego

et al. 2017

RAM

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Este artículo debe citarse como: Martínez-Aguilar NE, Vargas-Camaño ME, Hernández-Pliego RR, ChaiaSemerena GM, Pérez-Chavira MR. Inmunopatología de la enfermedad pulmonar obstructiva crónica. Rev Alerg Mex. 2017;64(3):327-346 AbstractChronic obstructive pulmonary disease (COPD) is a common, preventable and treatable condition that has a complex pathophysiology and an even more complex immunopathological process. The purpose of this review was to analyze COPD immunopathological aspects, which was addressed by undertaking a literature search for the most relevant documents indexed in the PubMed database over the last 10 years. Different conclusions could be drawn: in COPD immunopathology there are immune and non-immune inflammatory changes with oxidative stress imbalance, there are alterations in the protease/anti-protease ratio caused by direct and indirect genetic and epigeneticenvironmental defects; COPD produces irreversible tissue damage and chronic inflammation with tissue repair alteration, which induces chronic obstruction of the airway, bronchitis and systemic damage. Most common resulting comorbidities include cardiovascular disease, metabolic syndrome, osteoporosis, depression, musculoskeletal dysfunction, increased biological age, lung cancer and other types of malignancies. In the conception of COPD, recognizing that it is a nontransmittable and preventable disease is indispensable.

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Regulation of Immunoproteasome Function in the Lung

Cited by 54 publications

References 53 publications

Immunoproteasome deficiency is a feature of non-small cell lung cancer with a mesenchymal phenotype and is associated with a poor outcome

Immunoproteasome deficiency is a feature of non-small cell lung cancer with a mesenchymal phenotype and is associated with a poor outcome

Inhibition of Proteasome Activity Induces Formation of Alternative Proteasome Complexes

Inmunopatología de la enfermedad pulmonar obstructiva crónica

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