LRR-protein RNH1 dampens the inflammasome activation and is associated with COVID-19 severity

Abstract

Inflammasomes are cytosolic innate immune sensors of pathogen infection and cellular damage that induce caspase-1–mediated inflammation upon activation. Although inflammation is protective, uncontrolled excessive inflammation can cause inflammatory diseases and can be detrimental, such as in coronavirus disease (COVID-19). However, the underlying mechanisms that control inflammasome activation are incompletely understood. Here we report that the leucine-rich repeat (LRR) protein ribonuclease inhibitor (RNH1), which shares homology with LRRs of NLRP (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing) proteins, attenuates inflammasome activation. Deletion of RNH1 in macrophages increases interleukin (IL)-1β production and caspase-1 activation in response to inflammasome stimulation. Mechanistically, RNH1 decreases pro-IL-1β expression and induces proteasome-mediated caspase-1 degradation. Corroborating this, mouse models of monosodium urate (MSU)-induced peritonitis and lipopolysaccharide (LPS)-induced endotoxemia, which are dependent on caspase-1, respectively, show increased neutrophil infiltration and lethality in Rnh1−/− mice compared with wild-type mice. Furthermore, RNH1 protein levels were negatively related with disease severity and inflammation in hospitalized COVID-19 patients. We propose that RNH1 is a new inflammasome regulator with relevance to COVID-19 severity.

Ribonuclease inhibitor 1 (RNH1) deficiency cause congenital cataracts and global developmental delay with infection-induced psychomotor regression and anemia

“…Inflammasome activation, if not may thus be detrimental to the organism and may be involved in the tissue destruction observed in various inflammatory, autoimmune, autoinflammatory and age-related diseases [30,31]. A recent study has shown that RNH1 can attenuate inflammasome activation and thereby protects the organism from uncontrolled inflammasome activation [6]. It can therefore be speculated that infection-induced deterioration in our patients may be associated with lack of RNH1-mediated control of inflammasome activation.…”

“…The cytotoxicity of different ribonucleases correlates inversely with their affinity toward RNH1, implying that only ribonucleases that evade RNH1 may be cytotoxic and fatal to the cell [1]. In addition to this protective function, RNH1 has been hypothesized to be involved in several different cellular pathways such as protein translation regulation by various mechanisms [5], in modulating inflammatory response by reducing the inflammasome activation [6] and as a scavenger for reactive oxidative species [7,8]. Mice knockout for Rnh1 die in utero during embryonic stage E8.5-E10 due to impaired development of the hematopoietic system and anemia [9].…”

Human molecular genetics sheds light on the physiological significance of ribonuclease inhibitor (RNH1)

“…inhibitor 1 (OMIM 173320), is a 50-kDa protein that is expressed throughout the human tissues [1], with particularly high levels found in myeloid cells [2]. While it is mainly localized in the cytosol, it can also be found in the nucleus and mitochondria [3].…”

“…In addition, several other biological functions of RNH1 have been reported, such as involvement in cancer growth and metastasis [8], tiRNA degradation [9,10], microRNA (miR-21) processing [11], differentiation and myelination of oligodendrocytes [12] and inhibitor of oxidative damage [1,13]. Recent studies from Rnh1 knockout mice revealed that RNH1 is important for embryonic development [14], mRNA translation [15], hematopoiesis [14] and inflammation [2] and raised questions about the significance of RNase inhibitor function of RNH1 in vivo. Despite its routine application and extensive research over the last 50 years aimed at understanding its structure and functions, the exact significance of RNH1 in human physiology remains unknown.…”

“…However, the potential defects in neurons, muscles and eye lenses could not be examined in these E8.5 to E10 mouse embryos and may need further attention. In addition, Bombaci et al reported a haematopoietic-specific conditional Rnh1 −/− mouse model that bypassed the vulnerable embryonic phase [2]. They are viable and do not show gross phenotypic defects.…”