TIMP1/MMP tasapaino ja SIRTUIINI1: Raameissa COPD ja emfyseema

Abstract

Sirtuin1 (SIRT1), a protein/histone deacetylase, protects against the development of pulmonary emphysema. 

However, the molecular mechanisms underlying this observation remain elusive. The imbalance of tissue inhibitor of matrix metalloproteinases (TIMPs)/matrix metalloproteinases (MMPs) plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD)/emphysema.

 We hypothesized that SIRT1 protects against emphysema by redressing the imbalance between MMPs and TIMPs. 

To test this hypothesis, SIRT1 deficient and overexpressing/transgenic mice were exposed to cigarette smoke (CS). The protein level and activity of MMP-9 were increased in lungs of SIRT1 deficient mice exposed to CS as compared to WT littermates, which were attenuated by SIRT1 overexpression. SIRT1 deficiency decreased the level of TIMP-1, which was augmented in SIRT1 transgenic mice as compared to WT littermates by CS. However, the level of MMP-2, MMP-12, TIMP-2, TIMP-3, or TIMP-4 was not altered by SIRT1 in response to CS exposure. SIRT1 reduction was associated with imbalance of TIMP-1 and MMP-9 in lungs of smokers and COPD patients. 

Mass spectrometry and immunoprecipitation analyses revealed that TIMP-1 acetylation on specific lysine residues was increased, whereas its interaction with SIRT1 and MMP-9 was reduced in mouse lungs with emphysema, as well as in lungs of smokers and COPD patients. SIRT1 deficiency increased CS-induced TIMP-1 acetylation, and these effects were attenuated by SIRT1 overexpression. These results suggest that SIRT1 protects against COPD/emphysema via redressing the TIMP-1/MMP-9 imbalance involving TIMP-1 deacetylation. Thus, redressing the TIMP-1/MMP-9 imbalance by pharmacological activation of SIRT1 is an attractive approach in the intervention of COPD.

Kertauksena kaikki neljä TIMP ja niiden geenit

Kuvitella, niitä ei ole vieläkään enemmän kuin neljä kuten monta vuotta sitten. Tai sitten niitä ei ole kovin tarkkaan tutkittu. Ne ovat olleet aika huomaamattomia verrattuna MMP-joukon massiivisiin haitta-aikaansaannoksiin.

Niillä voi olla jokin muu oma funktio kuin vain olla MMPi.

 https://www.genenames.org/cgi-bin/genefamilies/set/892

Tissue inhibitor of metalloproteinase: The matrix metalloproteinases are inhibited by specific endogenous tissue inhibitors of metalloproteinases (TIMPs), which comprise a family of four protease inhibitors: TIMP1, TIMP2, TIMP3 and TIMP4. Overall, all MMPs are inhibited by TIMPs once they are activated but the gelatinases (MMP-2 and MMP- ) can form complexes with TIMPs when the enzymes are in the latent form. The complex of latent MMP-2 (pro-MMP-2)with TIMP-2 serves to facilitate the activation of pro-MMP-2 at the cell surface by MT1-MMP ( MMP-14 ), a membrane-anchored MMP. The role of the pro-MMP-9/TIMP-1 complex is still unknown. [Source: Wikipedia] 

Genes contained within the family: 4

l		TIMP1	TIMP1 metallopeptidase inhibitor 1 EPO, (Xp11.3)	TIMP2	TIMP 2metallopeptidase inhibitor 2 CSC-21K (17q25.3)	TIMP3	TIMP3 metallopeptidase inhibitor 3 SFD (22q12.3)	TIMP4	TIMP4 metallopeptidase inhibitor 4

TIMP-1

Function

Metalloproteinase inhibitor that functions by forming one to one complexes with target metalloproteinases, such as collagenases, and irreversibly inactivates them by binding to their catalytic zinc cofactor. Acts on MMP1, MMP2, MMP3, MMP7, MMP8, P9, MMP10, MMP11, MMP12, MMP13 and MMP16. Does not act on MMP14. Also functions as a growth factor that regulates cell differentiation, migration and cell death and activates cellular signaling cascades via CD63 and ITGB1. Plays a role in integrin signaling. Mediates erythropoiesis in vitro; but, unlike IL3, it is species-specific, stimulating the growth and differentiation of only human and murine erythroid progenitors.12 Publications

TIMP-2 

 

TIMP-3 

A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2.

Qi JH et al. Nat. Med. 2003 Apr;9(4):407-415

PMID: 12652295 Europe PMC Pubmed 

TACE, SIRT-1 ,TIMP-3, IBD, resveratroli

https://www.ncbi.nlm.nih.gov/pubmed/24548422

Cytokine. 2014 Mar;66(1):30-9. doi: 10.1016/j.cyto.2013.12.010. Epub 2014 Jan 4.

Involvement of TACE in colon inflammation: a novel mechanism of regulation via SIRT-1 activation.

Sharma M¹, Mohapatra J¹, Wagh A¹, Patel HM¹, Pandey D¹, Kadam S¹, Argade A², Deshpande SS³, Shah GB³, Chatterjee A⁴, Jain MR¹.

Abstract

TNF-α converting enzyme (TACE) processes the membrane TNF-α to release the bioactive soluble TNF-α. Several evidences suggest the involvement of TNF-α and TACE in inflammatory bowel disease (IBD). Tissue inhibitor of metalloproteinase (TIMP)-3, an endogenous inhibitor of TACE, is positively associated with silent information regulator (SIRT)-1. We aimed to study the expression of TACE, TIMP-3 and SIRT-1 at different stages of colitis and how TACE is regulated in response to SIRT-1 activation.

 Acute colitis was induced by 3.5% dextran sulfate sodium (DSS) in drinking water for 5days and levels of cytokines and mRNA expression of TACE, TIMP-3 and SIRT-1 were measured in colon at different time intervals. Next, the effect of SIRT-1 activator (resveratrol) or a selective TACE inhibitor (compound 11p) treatment was evaluated. Elevated levels of TNF-α, interleukin (IL)-6, IL-1β, interferon (IFN)-γ and IL-17 were observed during DSS exposure phase which restored to the normal level after DSS removal. A significant increase in TACE and suppression in TIMP-3 and SIRT-1 mRNA level was observed during DSS exposure phase which reverts back to normal towards the remission phase. Treatment with resveratrol significantly elevated SIRT-1 and TIMP-3 and suppressed TACE mRNA expression and was associated with amelioration of disease. Furthermore, treatment with selective TACE inhibitor significantly suppressed body weight loss, disease activity index, colonic myeloperoxidase activity and the elevated levels of cytokines after DSS challenge. These results strongly emphasize the involvement of TACE in colon inflammation and inhibition of TACE directly or indirectly via SIRT-1 activation ameliorates colitis.

KEYWORDS:

Inflammatory bowel disease; SIRT-1; TNF-α; TNF-α converting enzyme

PMID:

24548422

DOI:

10.1016/j.cyto.2013.12.010

ADAM17 ja EBOVgp

TACE/ADAM17 (2p25.1) uusimmat artikkelit PubMed . MUC1- sheddaasi

 2016 PubMed artikkeleita:  ADAM17/ TACE 

https://www.ncbi.nlm.nih.gov/gene/6868

Preferred Names

 a disintegrin and metalloproteinase domain-containing protein 17

Names

ADAM metallopeptidase domain 18

TNF-alpha convertase

TNF-alpha converting enzyme

snake venom-like protease

tumor necrosis factor, alpha, converting enzyme

Also known as

CSVP; TACE; NISBD; ADAM18; CD156B; NISBD1

Summary

This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biologic processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The encoded preproprotein is proteolytically processed to generate the mature protease. The encoded protease functions in the ectodomain shedding of tumor necrosis factor-alpha, in which soluble tumor necrosis factor-alpha is released from the membrane-bound precursor. This protease also functions in the processing of numerous other substrates, including cell adhesion proteins, cytokine and growth factor receptors and epidermal growth factor (EGF) receptor ligands. The encoded protein also plays a prominent role in the activation of the Notch signaling pathway. Elevated expression of this gene has been observed in specific cell types derived from psoriasis, rheumatoid arthritis, multiple sclerosis and Crohn's disease patients, suggesting that the encoded protein may play a role in autoimmune disease. [provided by RefSeq, Feb 2016]

Conserved Domains (4) summary

smart00050
Location:484 → 560

DISIN; Homologues of snake disintegrins

cd04270
Location:223 → 477

ZnMc_TACE_like; Zinc-dependent metalloprotease; TACE_like subfamily. TACE, the tumor-necrosis factor-alpha converting enzyme, releases soluble TNF-alpha from transmembrane pro-TNF-alpha.

pfam01562
Location:56 → 152

Pep_M12B_propep; Reprolysin family propeptide

pfam16698
Location:581 → 641

ADAM17_MPD; Membrane-proximal domain, switch, for ADAM17

 

Related articles in PubMed

1. A novel inhibitor of ADAM17 sensitizes colorectal cancer cells to 5-Fluorouracil by reversing Notch and epithelial-mesenchymal transition in vitro and in vivo. Li DD, et al. Cell Prolif, 2018 Oct. PMID 30069943
2. ADAM-17 is expressed in the inflammatory myopathy and is involved with interstitial lung disease. Nishimi A, et al. Clin Rheumatol, 2018 Apr. PMID 29411180
3. Short hairpin RNA-mediated gene silencing of ADAM17 inhibits the growth of breast cancer MCF‑7 cells in vitro and in vivo and its mechanism of action. Hu B, et al. Oncol Rep, 2018 Apr. PMID 29393483, Free PMC Article
4. ADAM17, a New Player in the Pathogenesis of Chronic Kidney Disease-Mineral and Bone Disorder. Perna AF, et al. J Ren Nutr, 2017 Nov. PMID 29056164
5. The shedding protease ADAM17: Physiology and pathophysiology. Zunke F, et al. Biochim Biophys Acta Mol Cell Res, 2017 Nov. PMID 28705384

See all (393) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. ADAM17 activation and secretion in the myeloid cells during HIV infection.
2. A novel ADAM17 inhibitor ZLDI-8 may be a potential chemosensitizer which sensitized CRC cells to 5-fluorouracil or irinotecan by reversing Notch and EMT pathways.
3. The isolated membrane proximal domain (MPD) of ADAM17 binds to phosphatidylserine (PS) but not to phosphatidylcholine liposomes. A cationic PS-binding motif is identified in this domain, replacement of which abrogates liposome-binding and renders the protease incapable of cleaving its substrates in cells.
4. ADAM-17 in inflammatory myopathy was significantly higher than that in healthy control. ADAM-17 in post-treatment with corticosteroid and/or immunosuppressant serum was significantly decreased compared with that in pre-treatment serum.
5. The present research suggests that ADAM17shRNA can inhibit MCF7 cell invasion and proliferation in vitro and inhibit MCF7 xenograft growth in vivo through the EGFR/PI3K/AKT and EGFR/MEK/ERK signaling pathways.
6. Uev1A-Ubc13 complex catalyzes lysine63-linked ubiquitination of RHBDF2 to promote TACE maturation.
7. ADAM17 plays a role in chronic kidney disease-mineral and bone disorder.
8. Insulin-like growth factor-1 activates different catalytic subunits p110 of PI3K in a cell-type-dependent manner to induce lipogenesis-dependent epithelial-mesenchymal transition through the regulation of ADAM10 and ADAM17.
9. ADAM17 is the main sheddase for the generation of human triggering receptor expressed in myeloid cells (hTREM2) ectodomain and cleaves TREM2 after Histidine 157. Findings reveal a link between shedding of TREM2 and its regulation during inflammatory conditions or chronic neurodegenerative disease in which activity or expression of sheddases might be altered.
10. Oxidative stress is correlated with hyperactivation of the ADAM17/Notch signaling pathway and a consequent increase in fibrosis in patients with endometriosis.

ADAM17 (TACE) substraatit , EBOV glykoproteiini joukossa

 2019 https://www.ncbi.nlm.nih.gov/pubmed/28893955/

NK -  Cytokiinit -  NKG2D akselista ADAM17 aktiivisuus lisääntyy ja TNF-alfaa vapautuu.

J Immunol. 2017 Oct 15;199(8):2865-2872. doi: 10.4049/jimmunol.1700647. Epub 2017 Sep 11.

NKG2D Signaling between Human NK Cells Enhances TACE-Mediated TNF-α Release.

Sharma N¹, Trinidad CV¹, Trembath AP¹, Markiewicz MA².  Abstract

NK group 2 member D (NKG2D) is a strong NK cell-activating receptor, with engagement by ligands triggering granule release and cytokine production. The function of NKG2D signaling in NK cells has largely been studied in the context of engagement of the receptor by ligands expressed on the surface of target cells. We report that upon activation with IL-12, IL-15, and IL-18 human NK cells express NKG2D ligands of the UL16 binding protein family on the cell surface. NKG2D-ligand interaction between cytokine-stimulated NK cells increases the activity of the metalloprotease TNF-α-converting enzyme (ADAM 17/TACE) . This enhanced TNF-α-converting enzyme activity significantly increases the release of TNF-α and UL16 binding protein from the surface of the NK cells. These results demonstrate that NKG2D signaling is critical for maximal TNF-α release by NK cells. Further, they demonstrate a role for NKG2D-ligand interaction via homotypic NK cell contact in NK cell effector function. Copyright © 2017 by The American Association of Immunologists, Inc.

 2018

https://www.sciencedirect.com/science/article/pii/S0167488917301878#t0005

1. Introduction

It was discovered in 1988 that the pro-inflammatory mediator tumor necrosis factor alpha (TNFα) was synthesized as a transmembrane protein, which needs to be proteolytically cleaved to be systemically active [1]. Since then, many researchers tried to identify the responsible proteolytic activity, which was believed to be an important therapeutic target. 

In 1994, it was reported that the TNFα cleaving enzyme was a metalloprotease (MMP), which could be inhibited by hydroxamic acid compounds. This hydroxamate not only reduced LPS-induced TNFα levels in vivo but also rescued mice from lethal septic shock confirming the TNFα cleaving enzyme being a promising therapeutic target [2].

(1997 ) Three years later, cDNAs coding for human and murine TNFα cleaving enzyme were cloned [3], [4], which showed that the enzyme is a membrane bound metalloprotease (MT-MMP) , which belonged to the family of disintegrin metalloproteases called adamalysins or ADAMs [5]. Subsequently, the TNFα cleaving enzyme was renamed ADAM17 [5].

ADAM17 knock-out animals turned out not to be viable [6]. Moreover, they showed an open eye phenotype at birth, which was reminiscent of mice lacking transforming growth factor alpha (TGFα), a ligand of the epidermal growth factor receptor (EGF-R). Since all ligands of the EGF-R are transmembrane proteins, which need to be cleaved in order to act systemically [7] it was hypothesized that ligands of the EGF-R were substrates of ADAM17 [6]. This was supported by data indicating that l-selectin, IL-6R and TGFα were processed by the same protease [8]. Meanwhile we know that ADAM17 has more than 80 substrates ranging from cytokines, growth factors, receptors to many cell adhesion molecules (Table 1) [9]. Therefore, it is not surprising that the biology of ADAM17 is complex and the protease is involved in the regulation of many body functions and developmental processes.

2. The shedding enzyme ADAM17

At least 10% of all cell surface proteins are believed to be proteolytically cleaved leading to the release of soluble proteins [10], [11]. As outlined above, ADAM17 was the first shedding protease to be molecularly characterized and it was shown to consist of an N-terminal signal sequence followed by a pro-domain, a metalloproteinase or catalytic domain, a disintegrin domain, a cysteine-rich membrane proximal domain, a single transmembrane domain and a cytoplasmic portion (Fig. 1) [3], [4].

Table 1. Substrates of ADAM17.

Immune system	Development, differentiation	Cell adhesion	Others
IL-1RII	TGFα	ALCAM	ACE-2
IL-6R	Hb-EGF	CD44	APP
IL-15R	AREG	CD62L (L-selectin)	APP-like protein2
CX3CL1 (fractalkine)	Epigen	Collagen XVII	Carbonic hydrolase 9
M-CSFR	EREG	Desmoglein 2	Prion protein
TNF-RI	NRG1	EpCam	Ebola virus glycoprotein
TNF-RII	FLT-3L	ICAM-1	EPCR
LDL-R	KL-1	JAM-A	GPIba
SORL1	KL-2	L1-CAM	GPV
SORT1	Jagged	NCAM	GPVI
SORCS1	DLL1	Nectin-4	Klotho
SORCS3	Notch1	SynCAM1	Muc-1, Episialin
TNFα	GH-R	VACM-1	NPR
Lymphotoxin α	IGF2-R		Pre-adipocyte factor
RANKL (TRANCE)	HER4 (ErbB4)		Ptprz
CSF-1	TrkA
TIM-1	VEGF-R2
TIM-3	LYPD3
TIM-4	PMEL17
MIC-A	PTP-LAR
MIC-B	SEMA4D
LAG-3	Syndecan1
CD16	Syndecan4
CD30 (TNFRSF8)	TEMEFF2
CD36	Vasorin
CD40 (TNFRSF5)
CD89
CD91 (APOER)
CD163
ICOS-L

MUC1 musiini, TACE ja MT-MMP

MUC1 tietoa lisää:

Cell Death Dis. 2014 Oct; 5(10): e1438.

MUC1 irtoaminen ”lehteily” tai ”hilseily” epiteelisolusta tyviosansa kompleksista ei tapahdu ilman säätelyä ja siinä säätelevät ” sheddase” entsyymit ovat MT-MMP ja TACE.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3189326/