ArticleThe Journal of experimental medicine2019
Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis.
Article in The Journal of experimental medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
21 citing papers in PubMed, 39 citations in OpenAlex.
- The N-terminal PA domains of signal-peptide-peptidase-like 2 (SPPL2) proteases impact on TNFα cleavage.Communications biology · 2025Article
- The Dectin-1 and Dectin-2 clusters: C-type lectin receptors with fundamental roles in immunity.EMBO reports · 2024Review
- Selective regulation of aspartyl intramembrane protease activity by calnexin.Cellular and molecular life sciences : CMLS · 2024Article
- Dynamic association of the intramembrane proteases SPPL2a/b and their substrates with tetraspanin-enriched microdomains.iScience · 2023Article
- The transmembrane domain of Frey1 harbors a transplantable inhibitory motif for intramembrane proteases.Cellular and molecular life sciences : CMLS · 2023Article
- ADAM10 and ADAM17, Major Regulators of Chronic Kidney Disease Induced Atherosclerosis?International journal of molecular sciences · 2023Review
- Endothelial ADAM10 controls cellular response to oxLDL and its deficiency exacerbates atherosclerosis with intraplaque hemorrhage and neovascularization in mice.Frontiers in cardiovascular medicine · 2023Article
- C11orf94/Frey is a key regulator for male fertility by controlling Izumo1 complex assembly.Science advances · 2022Article
- Phagosomal signalling of the C-type lectin receptor Dectin-1 is terminated by intramembrane proteolysis.Nature communications · 2022Article
- LOX-1 and cancer: an indissoluble liaison.Cancer gene therapy · 2021Review
- Non-canonical Shedding of TNFα by SPPL2a Is Determined by the Conformational Flexibility of Its Transmembrane Helix.iScience · 2020Article
- Physiological functions of SPP/SPPL intramembrane proteases.Cellular and molecular life sciences : CMLS · 2020Review
- Heme binding of transmembrane signaling proteins undergoing regulated intramembrane proteolysis.Communications biology · 2020Article
- Proteolytic Regulation of the Lectin-Like Oxidized Lipoprotein Receptor LOX-1.Frontiers in cardiovascular medicine · 2020Review
- Signaling Functions of Intramembrane Aspartyl-Proteases.Frontiers in cardiovascular medicine · 2020Review
- C-Type Lectin-Like Receptors: Head or Tail in Cell Death Immunity.Frontiers in immunology · 2020Review
- C-type lectin receptors of the Dectin-1 cluster: Physiological roles and involvement in disease.European journal of immunology · 2019Review
- Article
- HIV protease inhibitors block parasite signal peptide peptidases and prevent growth of Babesia microti parasites in erythrocytes.Biochemical and biophysical research communications · 2019Article
- LOX-1: Regulation, Signaling and Its Role in Atherosclerosis.Antioxidants (Basel, Switzerland) · 2019Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The lectin-like oxidized LDL receptor 1 (LOX-1) is a key player in the development of atherosclerosis. LOX-1 promotes endothelial activation and dysfunction by mediating uptake of oxidized LDL and inducing pro-atherogenic signaling. However, little is known about modulators of LOX-1-mediated responses. Here, we show that the function of LOX-1 is controlled proteolytically. Ectodomain shedding by the metalloprotease ADAM10 and lysosomal degradation generate membrane-bound N-terminal fragments (NTFs), which we identified as novel substrates of the intramembrane proteases signal peptide peptidase-like 2a and b (SPPL2a/b). SPPL2a/b control cellular LOX-1 NTF levels which, following self-association via their transmembrane domain, can activate MAP kinases in a ligand-independent manner. This leads to an up-regulation of several pro-atherogenic and pro-fibrotic targets including ICAM-1 and the connective tissue growth factor CTGF. Consequently, SPPL2a/b-deficient mice, which accumulate LOX-1 NTFs, develop larger and more advanced atherosclerotic plaques than controls. This identifies intramembrane proteolysis by SPPL2a/b as a novel atheroprotective mechanism via negative regulation of LOX-1 signaling.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.