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Last update 08 May 2025

HTRA2

Last update 08 May 2025

Basic Info

Synonyms

High temperature requirement protein A2, HtrA serine peptidase 2, HTRA2

+ [7]

Introduction

Serine protease that shows proteolytic activity against a non-specific substrate beta-casein (PubMed:10873535). Promotes apoptosis by either relieving the inhibition of BIRC proteins on caspases, leading to an increase in caspase activity; or by a BIRC inhibition-independent, caspase-independent and serine protease activity-dependent mechanism (PubMed:15200957). Cleaves BIRC6 and relieves its inhibition on CASP3, CASP7 and CASP9, but it is also prone to inhibition by BIRC6 (PubMed:36758104, PubMed:36758105). Cleaves THAP5 and promotes its degradation during apoptosis (PubMed:19502560). Seems to be proteolytically inactive.

Drugs associated with HTRA2

Ahp-10

Target

HTRA1 x HTRA2

Mechanism

HTRA1 inhibitors [+1]

Active Org.

University of Duisburg-Essen [+1]

Originator Org.

University of Duisburg-Essen

Active Indication

Dystrophy, Macular [+1]

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with HTRA2

100 Translational Medicine associated with HTRA2

0 Patents (Medical) associated with HTRA2

659

Literatures (Medical) associated with HTRA2

01 Apr 2025·The Journal of Molecular Diagnostics

Biomimetic Digital Twins and Multiomics

Article

Author: Brough, Dalton ; Du, Luke ; Glick, Joe ; Kearns, William G ; Stamoulis, Georgios ; Germain, Chandra ; Kearns, Laura ; Baisch, Lawrence ; Benner, Andrew

The National Academies of Sciences, Engineering, and Medicine issued a report on December 15, 2023, "Foundational Research Gaps and Future Directions for Digital Twins." This described the importance of using biomimetic digital twins and multiomics in research. These were incorporated in the current analysis of patients with rheumatoid arthritis (RA). Exome sequencing, genotype-phenotype ranking, and biomimetic digital twin analysis were used to identify five pathogenic and one likely pathogenic DNA variants in patient samples analyzed, which were absent from controls. The variants identified in these genes, P2RX7, HTRA2, PTPN22, FLG, CD46, and EIF4G1, play a role in the development of RA. Additionally, 3172 variants of unknown clinical significance (VUSs) were identified in patient samples, which were absent from controls. All VUSs appeared to be associated with RA. Hidden or dark data were identified from six genes. These genes, often found in patient samples, included HIF1A, HLA-DOA, PTGER3, HIPK3, TGFBR3, and HIF1A-AS3. VUSs identified in genes HIF1A, HLA-DOA, PTGER3, and HIPK3 were directly related to the pathogenesis of RA, whereas VUSs identified in genes TGFBR3 and HIF1A-AS3 were indirectly related. The current results suggest that biomimetic digital twins and multiomics can provide further insight into the development of RA. This may also potentially help with the process of reclassifying VUSs. The reclassification of VUSs will play a critical role in complex molecular diagnostics and drug development.

01 Feb 2025·Journal of Molecular Histology

UCF-101 ameliorates traumatic brain injury by promoting microglia M2 polarization via AMPK/NF-κB pathways in LPS-induced BV2 cells

Article

Author: Zhan, Cheng-Peng ; Chen, Gao ; Yu, Guo-Feng ; Wang, Ke-Wei ; Liu, Yong-Qi ; Yan, Xin-Jiang

Traumatic brain injury (TBI) is a common neurosurgical emergency. As a macrophage in brain, microglia involves in secondary TBI injury. UCF-101, an Omi/HtrA2 inhibitor, protects against neurological disorders. This study aims to investigate the effects of UCF-101 in TBI and its mechanism. Mouse microglia cell BV2 cells were exposed to 1 µg/mL LPS to construct TBI in vitro models. Following CCK8 assay, cells were treated with LPS + UCF-101 (2, 5, 10 µM), LPS + Compound C (AMPK inhibitor, 20 µM), and LPS + UCF-101 + Compound C groups. With lactate dehydrogenase (LDH) content detection, ELISA and qRT-PCR assays were used to measure proinflammatory factors. Biomarkers of M1 (CD16/32 and iNOS) and M2 phenotypes (CD206), as well as AMPK/NF-κB pathway-related protein expression were assessed by flow cytometry, immunofluorescence, and Western blot methods. There was a decrease in M1 phenotype biomarkers and an increase in M2 phenotype biomarkers after UCF-101 treatment. UCF-101 exposure reduced TNF-α, LDH, IL-1β, IL-6, IL-8, p-NF-κB p65/NF-κB p65, and activated p-AMPK α (T172)/AMPK α (T172) expression. Importantly, further Compound C treatment counteracted these effects of UCF-101. In conclusion, UCF-101 ameliorates TBI by promoting microglia M2 polarization via AMPK/NF-κB pathways in LPS-induced BV2 cells, providing solid scientific foundation for clinical application of UCF-101 in TBI treatment.

01 Feb 2025·Autophagy

Artificial targeting of autophagy components to mitochondria reveals both conventional and unconventional mitophagy pathways

Article

Author: Prescott, Alan R. ; Lorentzen, Katharina C. ; Ganley, Ian G.

Macroautophagy/autophagy enables lysosomal degradation of a diverse array of intracellular material. This process is essential for normal cellular function and its dysregulation is implicated in many diseases. Given this, there is much interest in understanding autophagic mechanisms of action in order to determine how it can be best targeted therapeutically. In mitophagy, the selective degradation of mitochondria via autophagy, mitochondria first need to be primed with signals that allow the recruitment of the core autophagy machinery to drive the local formation of an autophagosome around the target mitochondrion. To determine how the recruitment of different core autophagy components can drive mitophagy, we took advantage of the mito-QC mitophagy assay (an outer mitochondrial membrane-localized tandem mCherry-GFP tag). By tagging autophagy proteins with an anti-mCherry (or anti-GFP) nanobody, we could recruit them to mitochondria and simultaneously monitor levels of mitophagy. We found that targeting ULK1, ATG16L1 and the different Atg8-family proteins was sufficient to induce mitophagy. Mitochondrial recruitment of ULK1 and the Atg8-family proteins induced a conventional mitophagy pathway, requiring RB1CC1/FIP200, PIK3C3/VPS34 activity and ATG5. Surprisingly, the mitophagy pathway upon recruitment of ATG16L1 proceeded independently of ATG5, although it still required RB1CC1 and PIK3C3/VPS34 activity. In this latter pathway, mitochondria were alternatively delivered to lysosomes via uptake into early endosomes.Abbreviation: aGFP: anti-GFP nanobody; amCh: anti-mCherry nanobody; ATG: autophagy related; ATG16L1: autophagy related 16 like 1; AUTAC/AUTOTAC: autophagy-targeting chimera; BafA1: bafilomycin A₁; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CCCP: carbonyl cyanide m-chlorophenylhydrazone; COX4/COX IV: cytochrome c oxidase subunit 4; DFP: deferiprone; DMSO: dimethyl sulfoxide; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; HSPD1/HSP60: heat shock protein family D (Hsp60) member 1; HRP: horseradish peroxidase; HTRA2/OMI: HtrA serine peptidase 2; IB: immunoblotting; IF: immunofluorescence; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; NBR1: NBR1 autophagy cargo receptor; OMM: outer mitochondrial membrane; OPA1: OPA1 mitochondrial dynamin like GTPase; OPTN: optineurin; (D)PBS: (Dulbecco's) phosphate-buffered saline; PD: Parkinson disease; PFA: paraformaldehyde; POI: protein of interest; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; RAB: RAB, member RAS oncogene family; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SQSTM1: sequestosome 1; TAX1BP1: Tax1 binding protein 1; ULK: unc-51 like autophagy activating kinase 1; VPS: vacuolar protein sorting; WIPI: WD repeat domain, phosphoinositide interacting.

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HTRA2

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