Inflammation and Haematopoiesis
Ribonuclease Inhibitor (RNH1) or Ribonuclease/Angiogenin Inhibitor is a higher-vertebrate specific protein that contains leucine-rich repeats (LRRs). Conventionally, it binds to and inhibits ribonucleases. Interestingly, the LRRs of RNH1 are very similar to those of NLRP proteins. NLRP proteins belong to the NOD-like receptors (NLRs) family and form inflammasome complexes. However, the in vivo biological function of RNH1 is not entirely known. We have previously published that RNH1 is essential for embryonic development and erythropoiesis (Chennupati et. al JCI, 2018). Recently, we also identified that RNH1 regulates inflammation and inflammasome activation (Bombaci et.al bioRxiv, 2021). These findings have established that RNH1 is a critical player in inflammation and hematopoiesis. The fundamental aspects of this research project are to better understand the role of RNH1 in haematopoies and inflammation. In addition, such knowledge could establish the molecular basis for the development of novel therapeutic strategies for inflammatory and hematopoietic disorders.
Decreased embryonic erythropoiesis in ribonuclease inhibitor (Rnh1)-deficient mice. Morphology of E10 Rnh1+/– and Rnh1–/– whole embryos (Chennupati et al, JCI 2018).
mRNA specific translation and Ribosomopathies
Regulation of gene expression is important for normal development and is mainly controlled at the level of transcription. However, recent studies show that ribosomal proteins (RPs) regulate specific gene expression by selectively facilitating translation of specific mRNAs. Indeed, in Diamond- Blackfan anemia (DBA) and 5q– syndrome (Ribosomopathies), mutations in RP genes lead to a specific defect in erythroid gene translation and cause anemia. RPs are ubiquitously expressed and mutations in their genes should systemically affect translation, however RP gene mutations lead to hematopoietic-specific defects and the mechanism behind this is largely unknown. We recently published that RNH1 is a novel ribosomal associated protein – it binds to ribosomes and regulates erythropoiesis by regulating the translation of erythroid specific transcription factor GATA1. These findings reveal an unsuspected role for RNH1 in the control of GATA1 mRNA translation and erythropoiesis (JCI, 2018). Currently, we are interested in understanding the molecular mechanism of RNH1 in specific mRNA translation and its role in Ribosomopathies.
GATA1 is a very important erythroid transcription factor. RNH1 is a ribosomal associated protein that regulates GATA1 translation, which leads to efficient differentiation of progenitor cells to mature erythroid cells. Lack of RNH1 decreases GATA1 levels, which leads to an arrest in differentiation. (Chennupati et al, JCI 2018)
Inflammasomes in aging and myeloid malignancies
Inflammasomes are cytosolic innate immune receptors that upon activation form multiprotein caspase-1-activating complexes containing an adaptor protein ASC and caspase-1. Active caspase-1 processes the IL-1 cytokine members IL-1β and IL-18 and initiates Gasdermin-D (GASMD)-mediated pyroptosis. Recent studies suggest that involvement of Inflammasomes in age are associated with an increase in chronic inflammation (inflammaging) and myeloid malignancies. Myeloid malignancies, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), are heterogeneous disorders derived from myeloid stem and progenitor bone marrow cells. Genetically, they are very heterogeneous and characterized by uncontrolled proliferation and/or blockage of differentiation of abnormal myeloid progenitor cells. Our understanding of the genetic causes of these diseases has improved during the past decade by the identification of multiple driving somatic mutations and epigenetic alterations in MDS and AML patients. However, due to multiple interactions and the heterogeneity of the mutational landscape, the detailed pathophysiological mechanisms leading to MDS and subsequent progression to AML are still not fully understood. Currently, we are investigating the role and molecular mechanism of inflammasomes in myeloid malignancies and aging.