ArticleThe Journal of biological chemistry2016
A Novel Serpin Regulatory Mechanism: SerpinB9 IS REVERSIBLY INHIBITED BY VICINAL DISULFIDE BOND FORMATION IN THE REACTIVE CENTER LOOP.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 18 citations in OpenAlex.
- The Serpin Superfamily in Adipose Tissue Remodeling: Molecular Drivers of Immune-Metabolic Crosstalk and Insulin Sensitivity.Biology · 2026Review
- Single-cell sequencing combined with transcriptome sequencing to reveal the molecular mechanisms related to integrated stress responses in atherosclerosis.Journal of cardiothoracic surgery · 2026Article
- Identification of an Immunotherapy-Associated CD1cInternational journal of women's health · 2026Article
- Comparison of structures and inhibition activities of serine protease inhibitors of Trichinella spiralis and Trichinella pseudospiralis.Cell & bioscience · 2025Article
- Natural killer cell-derived exosome-based cancer therapy: from biological roles to clinical significance and implications.Molecular cancer · 2024Review
- The biological function of Serpinb9 and Serpinb9-based therapy.Frontiers in immunology · 2024Review
- Screening of four lysosome-related genes in sepsis based on RNA sequencing technology.BMC immunology · 2023Article
- Insights into the Mechanisms ofAntioxidants (Basel, Switzerland) · 2022Article
- Mesenchymal stem cells and natural killer cells interaction mechanisms and potential clinical applications.Stem cell research & therapy · 2022Review
- Article
- Single-cell RNA sequencing reveals compartmental remodeling of tumor-infiltrating immune cells induced by anti-CD47 targeting in pancreatic cancer.Journal of hematology & oncology · 2019Article
- Structural basis for the specificity of renin-mediated angiotensinogen cleavage.The Journal of biological chemistry · 2019Article
- Mesenchymal stromal cells of the bone marrow and natural killer cells: cell interactions and cross modulation.Journal of cell communication and signaling · 2018Article
- A pro-survival role for the intracellular granzyme B inhibitor Serpinb9 in natural killer cells during poxvirus infection.Immunology and cell biology · 2017Article
- From structure to redox: The diverse functional roles of disulfides and implications in disease.Proteomics · 2017Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The intracellular protease inhibitor Sb9 (SerpinB9) is a regulator of the cytotoxic lymphocyte protease GzmB (granzyme B). Although GzmB is primarily involved in the destruction of compromised cells, recent evidence suggests that it is also involved in lysosome-mediated death of the cytotoxic lymphocyte itself. Sb9 protects the cell from GzmB released from lysosomes into the cytosol. Here we show that reactive oxygen species (ROS) generated within cytotoxic lymphocytes by receptor stimulation are required for lyososomal permeabilization and release of GzmB into the cytosol. Importantly, ROS also inactivate Sb9 by oxidizing a highly conserved cysteine pair (P1-P1' in rodents and P1'-P2' in other mammals) in the reactive center loop to form a vicinal disulfide bond. Replacement of the P4-P3' reactive center loop residues of the prototype serpin, SERPINA1, with the P4-P5' residues of Sb9 containing the cysteine pair is sufficient to convert SERPINA1 into a ROS-sensitive GzmB inhibitor. Conversion of the cysteine pair to serines in either human or mouse Sb9 results in a functional serpin that inhibits GzmB and resists ROS inactivation. We conclude that ROS sensitivity of Sb9 allows the threshold for GzmB-mediated suicide to be lowered, as part of a conserved post-translational homeostatic mechanism regulating lymphocyte numbers or activity. It follows, for example, that antioxidants may improve NK cell viability in adoptive immunotherapy applications by stabilizing Sb9.
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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.