HtrA1 Mediated Intracellular Effects on Tubulin Using a Polarized RPE Disease Model

Oertle, Philipp; Trepp, Carolyn; Meistermann, Hélène; Burgoyne, Thomas; Sborgi, Lorenzo; Cortés-Cabrera, Álvaro; Chen, Chia-Yi; Hoflack, Jean-Christophe; Kam‐Thong, Tony; Badi, Laura; Flint, Nicholas; Ghiani, Zeynep Eren; Delobel, Frédéric; Stucki, Corinne; Gromo, Giulia; Einhaus, Alfred; Hornsperger, Benoit; Golling, Sabrina; Siebourg‐Polster, Juliane; Gerber, Françoise; Bohrmann, Bernd; Futter, Clare E.; Dunkley, Tom; Hiller, Sebastian; Schilling, Oliver; Enzmann, Volker; Fauser, Sascha; Plodinec, Marija; Iacone, Roberto

doi:10.1016/j.ebiom.2017.12.011

Cited by 17 publications

(17 citation statements)

References 71 publications

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“…Recent studies show that a promoter variant causing increased expression of HTRA1 in RPE cells leads to elevated levels of ECM proteins including HTRA1 substrates (Lin et al, ). Specifically, the HTRA1 substrates vitronectin, clusterin, Adam9, C3, and tubulin were also detected in the human RPE secretome (An et al, ; Melo et al, ). As the expression of Htra1 is elevated in our L‐ORD mouse models, we investigated the impact of the increased Htra1 on HTRA1 substrates in the RPE‐choroid of these mouse models using immunoblot analysis at the age of 3–6 months.…”

Section: Resultsmentioning

confidence: 99%

Late‐onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1

et al. 2019

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Late‐onset retinal degeneration (L‐ORD) is an autosomal dominant macular degeneration characterized by the formation of sub‐retinal pigment epithelium (RPE) deposits and neuroretinal atrophy. L‐ORD results from mutations in the C1q‐tumor necrosis factor‐5 protein (CTRP5), encoded by the CTRP5/C1QTNF5 gene. To understand the mechanism underlying L‐ORD pathology, we used a human cDNA library yeast two‐hybrid screen to identify interacting partners of CTRP5. Additionally, we analyzed the Bruch's membrane/choroid (BM‐Ch) from wild‐type (Wt), heterozygous S163R Ctrp5 mutation knock‐in (Ctrp5S163R/wt), and homozygous knock‐in (Ctrp5S163R/S163R) mice using mass spectrometry. Both approaches showed an association between CTRP5 and HTRA1 via its C‐terminal PDZ‐binding motif, stimulation of the HTRA1 protease activity by CTRP5, and CTRP5 serving as an HTRA1 substrate. The S163R‐CTRP5 protein also binds to HTRA1 but is resistant to HTRA1‐mediated cleavage. Immunohistochemistry and proteomic analysis showed significant accumulation of CTRP5 and HTRA1 in BM‐Ch of Ctrp5S163R/S163R and Ctrp5S163R/wt mice compared with Wt. Additional extracellular matrix (ECM) components that are HTRA1 substrates also accumulated in these mice. These results implicate HTRA1 and its interaction with CTRP5 in L‐ORD pathology.

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Section: Resultsmentioning

confidence: 99%

Late‐onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1

et al. 2019

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“…HtrA1 is predominantly secreted, but at least 20% of the HtrA1 pool is localized in the cytoplasm 34 . Intracellularly, it can be associated with microtubules and proteolytically process components of the cytoskeleton to regulate cell motility and alter mechanical cell phenotypes 35 , 36 . Moreover, HtrA1 degrades unfolded and misfolded proteins, thereby reducing the burden of unfolded proteins, contributing to proteostasis and cell survival 34 , 37 , 38 .…”

Section: Discussionmentioning

confidence: 99%

Cell density-dependent proteolysis by HtrA1 induces translocation of zyxin to the nucleus and increased cell survival

2020

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Proteases modulate critical processes in cutaneous tissue repair to orchestrate inflammation, cell proliferation and tissue remodeling. However, the functional consequences and implications in healing impairments of most cleavage events are not understood. Using iTRAQ-based Terminal Amine Isotopic Labeling of Substrates (TAILS) we had characterized proteolytic signatures in a porcine wound healing model and identified two neoN termini derived from proteolytic cleavage of the focal adhesion protein and mechanotransducer zyxin. Here, we assign these proteolytic events to the activity of either caspase-1 or serine protease HtrA1 and analyze the biological relevance of the resultant zyxin truncations. By cellular expression of full-length and truncated zyxin proteins, we demonstrate nuclear translocation of a C-terminal zyxin fragment that could also be generated in vitro by HtrA1 cleavage and provide evidence for its anti-apoptotic activities, potentially by regulating the expression of modulators of cell proliferation, protein synthesis and genome stability. Targeted degradomics correlated endogenous generation of the same zyxin fragment with increased cell density in human primary dermal fibroblasts. Hence, this newly identified HtrA1-zyxin protease signaling axis might present a novel mechanism to transiently enhance cell survival in environments of increased cell density like in wound granulation tissue.

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“…HtrA1 has recently been reported to have a non-proteolytic activity that enables it to disentangle Tau neurofibrillary tangles, suggesting that it can regulate the levels and aggregation of Tau. In the RPE, intracellular HtrA1 regulates degradation of tubulin [96]. Using RPE monolayer culture, the investigators also found degradation of tubulin results in impairment of phagocytotic activity of RPE cells [96].…”

Section: Intracellular Htra1 and Tubulinsmentioning

confidence: 96%

“…In the RPE, intracellular HtrA1 regulates degradation of tubulin [96]. Using RPE monolayer culture, the investigators also found degradation of tubulin results in impairment of phagocytotic activity of RPE cells [96].…”

Section: Intracellular Htra1 and Tubulinsmentioning

confidence: 96%

Asian age-related macular degeneration: from basic science research perspective

Yanagi

Foo

Yoshida

2018

Eye

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In Asian populations, polypoidal choroidal vasculopathy (PCV), a distinct phenotype of neovascular age-related macular degeneration (AMD), is more prevalent than Caucasians. Recently, there has been significant focus on how PCV differs from typical AMD. Although typical AMD and PCV share a variety of mechanisms by which abnormal angiogenic process occurs at the retinochoroidal interface, PCV has different clinical characteristics such as aneurysm-like dilation at the terminal of choroidal neovascular membranes, less frequent drusen and inner choroidal degeneration due to the thickened choroid. Recent studies support an important role for inflammation, angiogenesis molecules and lipid metabolism in the pathogenesis of neovascular AMD. Furthermore, although less attention has been paid to the role of the choroid in AMD, accumulating evidence suggests that the choriocapillaris and choroid also play a pivotal role in drusenogenesis, typical AMD and PCV. This review discusses the basic pathogenic mechanisms of AMD and explores the difference between typical AMD and PCV.

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HtrA1 Mediated Intracellular Effects on Tubulin Using a Polarized RPE Disease Model

Cited by 17 publications

References 71 publications

Late‐onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1

Late‐onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1

Cell density-dependent proteolysis by HtrA1 induces translocation of zyxin to the nucleus and increased cell survival

Asian age-related macular degeneration: from basic science research perspective

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