IL-6-STAT3 Controls Intracellular MHC Class II αβ Dimer Level through Cathepsin S Activity in Dendritic Cells

Kitamura, Hiroyuki; Kamon, Hokuto; Sawa, Shin Ichiro; Park, Sung Joo; Katunuma, Nobuhiko; Ishihara, Katsuhiko; Murakami, Masaaki; Hirano, Toshio

doi:10.1016/j.immuni.2005.09.010

Cited by 187 publications

(160 citation statements)

References 47 publications

(65 reference statements)

Supporting

Mentioning

143

Contrasting

Unclassified

Order By: Relevance

“…In this study, we found that eight different proteins interact with A2IC, by using a yeast twohybrid screen, including cathepsin S, SNX17, actin, RPS2, ZBTB4, OGDH, CCDC32, and PAPD4. An IL-6-gp130-STAT3-mediated increase in cathepsin S activity reduces the MHCII alpha/beta dimer in Dendritic cells and suppresses CD4 + T cell-mediated immune responses [23] . SNX17, a non-selfassembling protein, interacts with KRIT1, which plays a role in cell adhesion processes and intergrin signaling [24] .…”

Section: Discussionmentioning

confidence: 99%

Yeast two-hybrid screening of proteins interacting with plasmin receptor subunit: C-terminal fragment of annexin A2

Laumonnier

Syrovets

et al. 2011

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: To identify proteins that interact with the C-terminal fragment of annexin A2 (A2IC), generated by plasmin cleavage of the plasmin receptor, a heterotetramer (AA2t) containing annexin A2. Methods: The gene that encodes the A2IC fragment was obtained from PCR-amplified cDNA isolated from human monocytes, and was ligated into the pBTM116 vector using a DNA ligation kit. The resultant plasmid (pBTM116-A2IC) was sequenced with an ABI PRISM 310 Genetic Analyzer. The expression of an A2IC bait protein fused with a LexA-DNA binding domain (BD) was determined using Western blot analysis. The identification of proteins that interact with A2IC and are encoded in a human monocyte cDNA library was performed using yeast two-hybrid screening. The DNA sequences of the relevant cDNAs were determined using an ABI PRISM BigDye terminator cycle sequencing ready reaction kit. Nucleotide sequence databases were searched for homologous sequences using BLAST search analysis (http://www.ncbi.nlm.nih.gov). Confirmation of the interaction between the protein LexA-A2IC and each of cathepsin S and SNX17 was conducted using a small-scale yeast transformation and X-gal assay. Results: The yeast transformed with plasmids encoding the bait proteins were screened with a human monocyte cDNA library by reconstituting full-length transcription factors containing the GAL4-active domain (GAL4-AD) as the prey in a yeast two-hybrid approach. After screening 1×10 7 clones, 23 independent β-Gal-positive clones were identified. Sequence analysis and a database search revealed that 15 of these positive clones matched eight different proteins (SNX17, ProCathepsin S, RPS2, ZBTB4, OGDH, CCDC32, PAPD4, and actin which was already known to interact with annexin A2). Conclusion: A2IC A2IC interacts with various proteins to form protein complexes, which may contribute to the molecular mechanism of monocyte activation induced by plasmin. The yeast two-hybrid system is an efficient approach for investigating protein interactions.Keywords: yeast yeast two-hybrid system; human monocyte; plasmin receptor; C-terminal fragment of annexin A2 (A2IC); protein-protein interaction Acta

show abstract

Section: Discussionmentioning

confidence: 99%

Yeast two-hybrid screening of proteins interacting with plasmin receptor subunit: C-terminal fragment of annexin A2

Laumonnier

Syrovets

et al. 2011

Acta Pharmacol Sin

View full text Add to dashboard Cite

show abstract

“…In another study, IL-10, produced by BCG infected macrophages, reduced cathepsin S expression levels, thereby overriding the ability of IFN-g to enhance class II MHC levels and promote T-cell recognition of infected cells [44]. However, another study found that IL-10 (and IL-6) enhanced the activity of various cathepsins, including cathepsin S and that IL-6 diminished DM levels [45]. Conceivably, this may have accounted for the improved presentation of DM-sensitive ''cryptic'' T-cell epitopes in IL-6-treated DC [43,46].…”

Section: Reciprocal Relationships Between Cytokines and Lysosomal Catmentioning

confidence: 95%

Diverse regulatory roles for lysosomal proteases in the immune response

et al. 2009

View full text Add to dashboard Cite

The innate and adaptive immune system utilise endocytic protease activity to promote functional immune responses. Cysteine and aspartic proteases (cathepsins) constitute a subset of endocytic proteases, the immune function of which has been described extensively. Although historically these studies have focused on their role in processes such as antigen presentation and zymogen processing within the endocytic compartment, recent discoveries have demonstrated a critical role for these proteases in other intracellular compartments, and within the extracellular milieu. It has also become clear that their pattern of expression and substrate specificities are more diverse than was first envisaged. Here, we discuss recent advances addressing the role of lysosomal proteases in various aspects of the immune response. We pay attention to reports demonstrating cathepsin activity outside of its canonical endosome/lysosome microenvironment.Key words: Cathepsins . Endosomes . Immune regulation . Lysosomes IntroductionThe endosome/lysosome compartments, together with the cytosolic proteasomes, are the two major protein degradation systems in cells. Both have emerged as having many important regulatory functions in addition to their role in protein breakdown for amino acid recycling. For example, limited proteolysis within the endocytic pathway can induce activating conformational changes [1,2], release functional proteins from chaperones [3], and cleave soluble bioactive molecules from membrane-anchored precursors [4]. The concept of ''regulation through limited destruction'' is evident in many processes in innate and adaptive immunity. Endosome/lysosome-located proteases play key roles in antigen processing and presentation, cytokine regulation, NKT cell development, activation of serine protease zymogens in regulated secretory granules, integrin activation, induction of apoptosis and TLR signalling. Given that these processes may also be associated with undesirable immune responses and inflammation, the proteases involved may be considered as attractive drug targets. EnzymesEndosomes and lysosomes harbour mainly cysteine and aspartic acid proteases so-named because their active site utilises either a cysteine thiol or an aspartic acid as a key part of the catalytic site. Some endosome/lysosome located serine proteases such as cathepsin G, granzymes and thymus specific serine protease (TSSP) have important roles in the immune system; however, we focus primarily here on the cysteine and aspartic proteases. Most of the lysosomal cysteine proteases are related to papain and belong to the so-called C1 family. These include cathepsins L, S, C, F, H, B, X, K, V and W. Cathepsins D and E are also found in lysosomes but are aspartic acid proteases related to pepsin. An additional cysteine protease is found in lysosomes, which is more closely related to the caspases. This is asparaginyl endopeptidase (AEP) or legumain, a member of the C13 family. Some of these enzymes are endopeptidases (cathepsins S, L, K, F, V, D, E and AEP), where...

show abstract

“…Although the cathepsin S promoter does not have a respectable STAT binding site, cathepsin S expression in VSMC was activated by IL-6 in a STAT-3-dependent process [37], which probably involved upregulation of IRF proteins. Indeed, mRNA for IRF-8 and IRF-3 were increased in the ascending aorta of MPS I mice, and these proteins may function in a similar fashion on the cathepsin S promoter as IRF-1 [27].…”

Section: Role Of Stat Proteins In Upregulation Of Mmp-12 and Cathepsin Smentioning

confidence: 97%

Upregulation of elastase proteins results in aortic dilatation in mucopolysaccharidosis I mice

Tittiger

Knutsen

et al. 2008

Molecular Genetics and Metabolism

View full text Add to dashboard Cite

Mucopolysaccharidosis I (MPS I), known as Hurler syndrome in the severe form, is a lysosomal storage disease due to -L-iduronidase (IDUA) deficiency. It results in fragmentation of elastin fibers in the aorta and heart valves via mechanisms that are unclear, but may result from the accumulation of the glycosaminoglycans heparan and dermatan sulfate. Elastin fragmentation causes aortic dilatation and valvular insufficiency, which can result in cardiovascular disease. The pathophysiology of aortic disease was evaluated in MPS I mice. MPS I mice have normal elastic fiber structure and aortic compliance at early ages, which suggests that elastin assembly is normal. Elastin fragmentation and aortic dilatation are severe at 6 months, which is temporally associated with marked increases in mRNA and enzyme activity for two elastin-degrading proteins, matrix metalloproteinase-12 (MMP-12) and cathepsin S. Upregulation of these genes likely involves activation of STAT proteins, which may be induced by structural stress to smooth muscle cells from accumulation of glycosaminoglycans in lysosomes. Neonatal intravenous injection of a retroviral vector normalized MMP-12 and cathepsin S mRNA levels and prevented aortic disease. We conclude that aortic dilatation in MPS I mice is likely due to degradation of elastin by MMP-12 and/or cathepsin S. This aspect of disease might be ameliorated by inhibition of the signal transduction pathways that upregulate expression of elastase proteins, or by inhibition of elastase activity. This could result in a treatment for patients with MPS I, and might reduce aortic aneurism formation in other disorders.

show abstract

IL-6-STAT3 Controls Intracellular MHC Class II αβ Dimer Level through Cathepsin S Activity in Dendritic Cells

Cited by 187 publications

References 47 publications

Yeast two-hybrid screening of proteins interacting with plasmin receptor subunit: C-terminal fragment of annexin A2

Yeast two-hybrid screening of proteins interacting with plasmin receptor subunit: C-terminal fragment of annexin A2

Diverse regulatory roles for lysosomal proteases in the immune response

Upregulation of elastase proteins results in aortic dilatation in mucopolysaccharidosis I mice

Contact Info

Product

Resources

About