HTRA proteases: regulated proteolysis in protein quality control

Clausen, Tim; Kaiser, Markus; Huber, Robert; Ehrmann, Michael

doi:10.1038/nrm3065

Cited by 429 publications

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“…To date, four HTRA1 family members have been identified and are termed HTRA1, HTRA2, HTRA3, and HTRA4. HTRA2 is the best characterized of the four and exists as a membrane protein primarily involved in mitochondrial quality control [2,3]. Both HTRA1 and HTRA2 are primarily regarded as being key regulators of tumor development and subsequent malignancies [4][5][6], although a growing body of evidence now exists to suggest that HTRA1 may also play a central role in musculoskeletal development and disease through its proteolytic actions on proteins within the extracellular matrix (ECM) [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…Mammalian high-temperature requirement serine protease A1 (HTRA1) belongs to a well-defined group of serine proteases originally identified in bacteria [1,2]. They share many common features including a highly conserved trypsin-like serine protease domain and at least one Post synaptic density protein, Drosophila disc large tumor suppressor, and Zonula occludens-1 protein domain at the C terminus.…”

Section: Introductionmentioning

confidence: 99%

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Human Serine Protease HTRA1 Positively Regulates Osteogenesis of Human Bone Marrow-derived Mesenchymal Stem Cells and Mineralization of Differentiating Bone-forming Cells Through the Modulation of Extracellular Matrix Protein

et al. 2012

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Mammalian high-temperature requirement serine protease A1 (HTRA1) is a secreted member of the trypsin family of serine proteases which can degrade a variety of bone matrix proteins and as such has been implicated in musculoskeletal development. In this study, we have investigated the role of HTRA1 in mesenchymal stem cell (MSC) osteogenesis and suggest a potential mechanism through which it controls matrix mineralization by differentiating boneforming cells. Osteogenic induction resulted in a significant elevation in the expression and secretion of HTRA1 in MSCs isolated from human bone marrow-derived MSCs (hBMSCs), mouse adipose-derived stromal cells (mASCs), and mouse embryonic stem cells. Recombinant HTRA1 enhanced the osteogenesis of hBMSCs as evidenced by significant changes in several osteogenic markers including integrin-binding sialoprotein (IBSP), bone morphogenetic protein 5 (BMP5), and sclerostin, and promoted matrix mineralization in differentiating boneforming osteoblasts. These stimulatory effects were not observed with proteolytically inactive HTRA1 and were abolished by small interfering RNA against HTRA1. Moreover, loss of HTRA1 function resulted in enhanced adipogenesis of hBMSCs. HTRA1 Immunofluorescence studies showed colocalization of HTRA1 with IBSP protein in osteogenic mASC spheroid cultures and was confirmed as being a newly identified HTRA1 substrate in cell cultures and in proteolytic enzyme assays. A role for HTRA1 in bone regeneration in vivo was also alluded to in bone fracture repair studies where HTRA1 was found localized predominantly to areas of new bone formation in association with IBSP. These data therefore implicate HTRA1 as having a central role in osteogenesis through modification of proteins within the extracellular matrix. STEM CELLS

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human Serine Protease HTRA1 Positively Regulates Osteogenesis of Human Bone Marrow-derived Mesenchymal Stem Cells and Mineralization of Differentiating Bone-forming Cells Through the Modulation of Extracellular Matrix Protein

et al. 2012

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“…MMP proteolysis of aggrecan has been demonstrated to be mainly a process of normal turnover in the disc, and evidence suggests that cathepsin K also has a significant role in normal turnover (19). HTRA1 is a serine protease initially described in bacteria (20). Several substrates have been described for HTRA1, including fibronectin, type II collagen, decorin, aggrecan, elastin, bone sialoprotein, and matrix Gla protein (21).…”

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confidence: 99%

Chondroadherin Fragmentation Mediated by the Protease HTRA1 Distinguishes Human Intervertebral Disc Degeneration from Normal Aging

Akhatib

Önnerfjord

Gawri

et al. 2013

Journal of Biological Chemistry

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Background:Little is known about the molecular mechanisms involved in intervertebral disc degeneration (IVD). Results: CHAD fragmentation is found only in degenerate IVDs. HTRA1 is capable of generating the in vivo fragment. Conclusion: CHAD fragmentation can be a marker of degeneration, distinguishing between aging and degeneration. Significance: Inhibiting HTRA1 activity could be of value to slow down disc degeneration without influencing normal turnover.

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“…22 HtrA2 (also known as Omi) is an ATP-independent serine protease structurally and functionally related to the bacterial quality control proteases DegP and DegS. 23 HtrA2 resides in the intermembrane space of the mitochondrion, and its loss leads to accumulation of unfolded proteins in the mitochondria, oxidative stress, and defective mitochondrial respiration, 24 suggesting that, like its bacterial counterparts, HtrA2 functions as a quality control protease. Mice lacking HtrA2 protease activity as a result of missense mutation (mnd2 mice) or targeted deletion (HtrA2 knockout mice) of the HtrA2 (Prss25) gene exhibit early onset neurodegeneration and motor abnormalities similar to Parkinson's disease, and die between postnatal day (dP) 30 and dP40.…”

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Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

et al. 2012

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mnd2 mice die prematurely as a result of neurodegeneration 30-40 days after birth due to loss of the enzymatic activity of the mitochondrial quality control protease HtrA2/Omi. Here, we show that transgenic expression of human HtrA2/Omi in the central nervous system of mnd2 mice rescues them from neurodegeneration and prevents their premature death. Interestingly, adult transgenic mnd2 mice develop accelerated aging phenotypes, such as premature weight loss, hair loss, reduced fertility, curvature of the spine, heart enlargement, increased autophagy, and death by 12-17 months of age. These mice also have elevated levels of clonally expanded mitochondrial DNA (mtDNA) deletions in their tissues. Our results provide direct genetic evidence linking mitochondrial protein quality control to mtDNA deletions and aging in mammals. Cell Death and Differentiation (2013) 20, 259-269; doi:10.1038/cdd.2012 published online 14 September 2012 Mitochondria are dynamic organelles primarily involved in the production of adenosine triphosphate (ATP) through oxidative phosphorylation. They also play important roles in diverse cellular processes such as cell death, autophagy and innate immunity. 1 As a consequence of oxidative phosphorylation, mitochondria produce reactive oxygen species (ROS), which damages mitochondrial proteins, lipids and nucleic acids, because of their proximity to the source of ROS production. Accumulation over time of mutations and deletions in mitochondrial DNA (mtDNA) together with increased protein misfolding, as a result of ROS damage, leads to ageassociated decline in mitochondrial function, which is believed to be responsible for organismal aging and age-associated diseases. [2][3][4] To maintain optimal mitochondrial function over time, a number of quality control mechanisms exist that monitor and regulate all aspects of mitochondrial physiology. Damaged and unfolded mitochondrial proteins are removed by mitochondrial quality control proteases, which recognize these proteins and degrade them. 5,6 The ATP-dependent AAA (ATPase-Associated with diverse cellular Activities) proteases, are among the best-characterized proteases implicated in mitochondrial protein quality control. 7 The AAA proteases, ClpXP and Lon, located in the matrix are involved in quality control of matrix proteins. Although no specific mitochondrial substrate has been identified for the ClpXP protease, in vitro studies showed that Lon protease preferentially targets oxidatively damaged matrix aconitase. 8 Two additional AAA proteases, Paraplegin (encoded by the SPG7 gene) and YME1L, are associated with the inner membrane with their catalytic sites facing the matrix and intermembrane space, respectively. 7 These proteases are believed to be primarily involved in the degradation of damaged and unfolded membrane proteins of the electron transport chain. In addition, Paraplegin has been shown to process the mitochondrial ribosomal protein MrpL32, 9 suggesting that it might also function in mitochondrial ribosome assembly. Loss-of-functi...

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HTRA proteases: regulated proteolysis in protein quality control

Cited by 429 publications

References 99 publications

Human Serine Protease HTRA1 Positively Regulates Osteogenesis of Human Bone Marrow-derived Mesenchymal Stem Cells and Mineralization of Differentiating Bone-forming Cells Through the Modulation of Extracellular Matrix Protein

Human Serine Protease HTRA1 Positively Regulates Osteogenesis of Human Bone Marrow-derived Mesenchymal Stem Cells and Mineralization of Differentiating Bone-forming Cells Through the Modulation of Extracellular Matrix Protein

Chondroadherin Fragmentation Mediated by the Protease HTRA1 Distinguishes Human Intervertebral Disc Degeneration from Normal Aging

Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

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