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Role of Ribonuclease inhibitor (RNH1) in Hematopoiesis and Inflammation

English title Role of Ribonuclease inhibitor (RNH1) in Hematopoiesis and Inflammation
Applicant Allam Ramanjaneyulu
Number 157486
Funding scheme SNSF Professorships
Research institution Universitätsklinik für Hämatologie und Hämatologisches Zentrallabor Inselspital
Institution of higher education University of Berne - BE
Main discipline Pathophysiology
Start/End 01.04.2015 - 31.03.2019
Approved amount 1'518'766.00
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All Disciplines (3)

Discipline
Pathophysiology
Immunology, Immunopathology
Biochemistry

Keywords (6)

Innate immunity; Inflammasomes; Haematopoiesis; Erythropoiesis; Anemia; Inflammation

Lay Summary (French)

Lead
L'inhibiteur de ribonuclease-I (RNH-1) est un facteur intervenant dans la régulation de l'hématopoïèse et la modulation de la réponse inflammatoire. Notre projet consiste à découvrir les mécanismes moléculaires d'action de la protéine RNH-1 dans ces deux processus. Les applications cliniques des résultats seront également mis en valeur.
Lay summary

L'hématopoïèse est un processus complexe qui permet la génération de différentes lignées d'érythrocytes matures à partir de cellules souches hématopoïétiques pluripotentes (HSCs). Plusieurs maladies hématologiques proviennent d'une altération de ce mécanisme. L'inflammation est une réponse coordonnée du système immunitaire à différentes attaques de l'organisme comme les infections, les lésions cellulaires ou les irritations. De récentes études suggèrent que l'inflammation influence l'hématopoièse, des inflammations chroniques pouvant contribuer au développement de cellules hématopoïétiques malignes. Il est donc crucial de mieux comprendre les interactions entre ces deux mécanismes que sont l'hématopoïèse et l'inflammation. 

L'inhibiteur de ribonuclease-1 (RNH-1) est une protéine cytosolique connue pour inhiber les ribonucléases. Nous avons récemment identifié RNH-1 comme une nouvelle protéine associée au complexe ribosomal, contrôlant l'érythropoïèse en modulant la traduction de facteurs de transcriptions spécifiques à ce processus. Il semble également que RNH-1 inhibe l'inflammation en diminuant sa plateforme cellulaire d'activation: l'inflammasome. Ces résultats nous portent à croire que RNH-1 est un nouveau facteur clé dans les mécanismes d'hématopoièse et d'inflammation.

 Cette demande a pour but de mieux comprendre les différents aspects des mécanismes moléculaires dans lesquels est impliqué la protéine RNH-1, que ce soit dans l'activation de l'inflammasome, la biologie des ribosomes ou l'hématopoièse. Nous nous attacherons particulièrement à comprendre le rôle de RNH-1 dans les ribosomopathies.

 Les connaissances fondamentales issues de cette étude nous donneront une meilleure compréhension du rôle de la protéine RNH-1 dans l'hématopoïèse et l'inflammation. De nouvelles découvertes pourraient établir les bases moléculaires  nécessaires à l'établissement de nouvelles stratégies thérapeutiques contre les maladies inflammatoires ou les troubles hématopoïètiques.

 

 

Direct link to Lay Summary Last update: 20.03.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine
Chanias Ioannis, Stojkov Kristina, Stehle Gregor Th., Daskalakis Michael, Simeunovic Helena, Njue Linet Muthoni, Schnegg-Kaufmann Annatina S., Porret Naomi A., Allam Ramanjaneyulu, Rao Tata Nageswara, Benz Rudolf, Ruefer Axel, Schmidt Adrian, Adler Marcel, Rovo Alicia, Balabanov Stefan, Stuessi Georg, Bacher Ulrike, Bonadies Nicolas (2021), Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine, in Cancers, 13(13), 3296-3296.
Angiogenin (ANG)—Ribonuclease Inhibitor (RNH1) System in Protein Synthesis and Disease
Sarangdhar Mayuresh Anant, Allam Ramanjaneyulu (2021), Angiogenin (ANG)—Ribonuclease Inhibitor (RNH1) System in Protein Synthesis and Disease, in International Journal of Molecular Sciences, 22(3), 1287-1287.
LRR protein RNH1 inhibits inflammasome activation through proteasome-mediated degradation of Caspase-1 and is associated with adverse clinical outcomes in COVID-19 patients
G Bombaci, MA Sarangdhar, N Andina, A Tardivel, EC Yu, GM Mackie, M Pugh, VB Ozan, Y Banz, T Spinetti, C Hirzel, E Youd, JC Schefold, G Taylor, R Allam (2021), LRR protein RNH1 inhibits inflammasome activation through proteasome-mediated degradation of Caspase-1 and is associated with adverse clinical outcomes in COVID-19 patients, 1.
Increased cardiovascular comorbidities in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia presenting with systemic inflammatory and autoimmune manifestations
Kipfer B., Daikeler T., Kuchen S., Hallal M., Andina N., Allam R., Bonadies N. (2018), Increased cardiovascular comorbidities in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia presenting with systemic inflammatory and autoimmune manifestations, in Seminars in Hematology, 55(4), 242-247.
Ribonuclease inhibitor 1 regulates erythropoiesis by controlling GATA1 translation
Chennupati Vijaykumar, Veiga Diogo F.T., Maslowski Kendle M., Andina Nicola, Tardivel Aubry, Yu Eric Chi-Wang, Stilinovic Martina, Simillion Cedric, Duchosal Michel A., Quadroni Manfredo, Roberts Irene, Sankaran Vijay G., MacDonald H. Robson, Fasel Nicolas, Angelillo-Scherrer Anne, Schneider Pascal, Hoang Trang, Allam Ramanjaneyulu (2018), Ribonuclease inhibitor 1 regulates erythropoiesis by controlling GATA1 translation, in Journal of Clinical Investigation, 128(4), 1597-1614.

Collaboration

Group / person Country
Types of collaboration
Fabio Martinon/Dept of Biochemistry-University of Lausanne Switzerland (Europe)
- Publication
- Research Infrastructure
Trang Hoang/Institute of Research in Immunology and Cancer, University of Montreal, Canada Canada (North America)
- Publication
- Research Infrastructure
- Exchange of personnel
Pascal Schneider/ Dept of Biochemistry-University of Lausanne Switzerland (Europe)
- Publication
- Research Infrastructure
- Exchange of personnel
Anne Angelillo-Scherre/Klinik für Hämatologie&Hämatologisches Zentrallabor,Inselspital, Bern Switzerland (Europe)
- Publication
- Research Infrastructure
- Exchange of personnel
Vijay G. Sankaran/Harvard Medical School,Boston United States of America (North America)
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
61st American Society of Haematology (ASH) Annual Meeting Talk given at a conference Higher Vertebrate Specific Gene Ribonuclease Inhibitor (RNH1) Is Essential for Adult Hematopoietic Stem Cell Function and Cell Cycle Regulation 07.12.2019 Orlando, United States of America Allam Ramanjaneyulu;
ISEH 48th Annual Scientific Meeting 2019 Talk given at a conference Ribonuclease Inhibitor (RNH1) regulates hematopoietic cell specific translation 24.08.2019 Brisbane, Australia Stilinovic Martina;
Wolfsberg immunology meeting Poster The leucine-rich repeat (LRR) protein, Ribonuclease inhibitor (RNH1) limits the NLRP3 inflammasome activation. 13.03.2019 spiez, Switzerland Allam Ramanjaneyulu;
EMBO workshop, The Inflammsomes Poster The leucine-rich repeat (LRR) protein, Ribonuclease inhibitor (RNH1) limits the NLRP3 inflammasome activation 25.09.2018 Munich, Germany Tardivel Aubry; Allam Ramanjaneyulu;
Swiss Society of Hematology Talk given at a conference Ribonuclease Inhibitor (RNH1) regulates erythropoiesis by controlling GATA1-specific mRNA translation 27.06.2018 zurich, Switzerland Stilinovic Martina; Allam Ramanjaneyulu;
Invited Talk 2018 Individual talk Ribonuclease Inhibitor -1 in selective mRNA translation and erythropoiesis 09.03.2018 Basel, Switzerland Allam Ramanjaneyulu;
The Day of BioMedical Research 2017 Poster The Ribonuclease inhibitor protein (RNH1) limits the inflammasome activation 31.10.2017 Bern, Switzerland Tardivel Aubry; Allam Ramanjaneyulu;
The Day of BioMedical Research 2017 Poster Ribonuclease Inhibitor is a ribosome-associated Protein and regulates erythropoiesis by controlling GATA1-specific mRNA translation 31.10.2017 Bern, Switzerland Stilinovic Martina; Tardivel Aubry;
Protein Synthesis and Translational Control 2017 Talk given at a conference Ribonuclease Inhibitor (RNH1) is a ribosome-associated protein and regulates erythropoiesis by controlling GATA1-specific mRNA translation 06.09.2017 EMBL, Heidelberg, Germany Allam Ramanjaneyulu;
ISEH 46th Annual Scientific Meeting 2017 Poster ibonuclease Inhibitor (RNH1) is a ribosome-associated protein and regulates erythropoiesis by controlling GATA1-specific mRNA translation 24.08.2017 Frankfurt, Germany Allam Ramanjaneyulu;
Stem cell seminar 2016 Individual talk Selective mRNA translation by Ribonuclease Inhibitor 12.07.2016 Bern, Switzerland Allam Ramanjaneyulu;
SGIM Jahresversammlung 2015 Talk given at a conference An Unexpected Role for Ribonuclease Inhibitor (RNH1) in Erythropoiesis 21.05.2015 Basel, Switzerland Allam Ramanjaneyulu;


Awards

Title Year
ISEH travel grant 2019
Poster Prize_PreClinical_Day of Clinical Research 2017 2017

Associated projects

Number Title Start Funding scheme
190073 Role of Ribonuclease inhibitor (RNH1) in Hematopoiesis and Inflammation 01.04.2020 SNSF Professorships
183721 Role of Ribonuclease inhibitor (RNH1) in Hematopoiesis and Inflammation 01.04.2019 SNSF Professorships
183721 Role of Ribonuclease inhibitor (RNH1) in Hematopoiesis and Inflammation 01.04.2019 SNSF Professorships
183501 Installing a Hyperion CyTOF mass cytometry platform for high-dimensional single cell analysis at the University of Bern 01.10.2019 R'EQUIP

Abstract

Ribonuclease Inhibitor (RNH1) is an ubiquitously expressed 50-kDa leucine-rich repeat (LRR) protein. It is mainly localized in the cytosol, but can also be found in the nucleus and mitochondria. The human RNH1 gene evolved via gene duplication and is conserved among mammalian species. As suggested by its name, RNH1 binds to and inhibits pancreatic type ribonucleases. Further, RNH1 contains numerous cysteine residues whose sulfhydryl groups might play key structural roles and protect from oxidative damage. Despite of all these observations, the function of RNH1 in vivo remains unexplored. Interestingly, the LRRs of RNH1 are very similar to those of NLRP proteins. NLRP proteins belong to NOD-like receptors (NLRs) family and form inflammasome complexes. Inflammasomes are caspase-1 activating complexes and they process IL-1 members IL-1ß, IL-18 and IL-33 cytokines. Whether RNH1 plays a role in inflammasome activation needs to be established.We recently identified two important functions of RNH1. First, we discovered that RNH1 regulates erythropoiesis by binding to ribosomal proteins and substantiates the translation of erythroid specific genes. Loss of RNH1 led to a severe decrease in erythroid cell maturation, resulting in the death of mice at embryonic day E8.5 to E10. These findings have high translational relevance, since it is known that mutations in ribosomal proteins cause i) macrocytic anemia in Diamond-Blackfan anemia (DBA), a congenital bone marrow failure syndrome, and ii) 5q-syndrome, a subtype of myelodysplastic syndrome (MDS). Interestingly, it has been shown that ribosomal deficiency in DBA patients specifically cause decrease in GATA1 translation. Our results suggest that RNH1 stabilizes ribosomes and that its deficiency leads to a defect in GATA1 translation and to a decrease in erythropoiesis, similarly to what is observed in DBA patients. A second important function of RNH1 that we recently uncovered is that it negatively regulates inflammasome activation by direct binding to NLRP proteins, suggesting that RNH1 inhibits inflammation. Collectively, these findings have introduced RNH1 as a novel player in hematopoiesis and inflammation. The long-term goal of this proposal is to understand how RNH1 regulates hematopoiesis and inflammation. Three complementary research sub-projects were designed to elucidate molecular mechanisms of RNH1 action. The first sub-project will investigate the role of RNH1 in erythropoiesis by focusing on how RNH1 affects ribosome biology, translation of erythroid specific genes and erythroid maturation. We will also investigate a potential role of RNH1 in the pathology of DBA and 5q-syndrome. The second sub-project will study the molecular mechanism of RNH1 in the regulation of inflammasome activation and inflammation. The third sub-project will focus on the role of RNH1 in inflammation-induced hematopoiesis and hematopoietic stem cell (HSC) function, differentiation of other hematopoietic lineages and possibly malignancies of HSCs.Results from these studies will provide a better understanding of RNH1 in the regulation of hematopoiesis and inflammation. Moreover, our results will aid the development of therapies to treat patients with inflammatory disorders, hematopoietic malignancies and erythropoiesis disorders that are caused by ribosomal deficiency.
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