A glimpse on metazoan ZNFX1 helicases, ancient players of antiviral innate immunity

Blasi, Giulia; Bortoletto, Enrico; Gasparotto, Matteo; Filippini, F.; Bai, Changming; Rosani, Umberto; Venier, Paola

doi:10.1016/j.fsi.2022.01.019

Cited by 7 publications

(3 citation statements)

References 95 publications

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“…Interestingly, the closest relative to the HELZ2 helicase domain 1 and 2 is found in the HELZ protein that has been shown to promote mRNA translation repression and decay (54). Some other members of the Upf1-like subgroup of helicases such as ZNFX1, MOV10 and MOV10L1 interfere with viral infections and/or dispersion of mobile elements (55–57) It is noteworthy that, like HELZ2, ZNFX1 and MOV10 are also interferon-inducible proteins (Fig. 2, (58)).…”

Section: Discussionmentioning

confidence: 99%

HELZ2: a new, interferon-regulated, human 3’-5’ exoribonuclease of the RNB family is expressed from a non-canonical initiation codon

Huntzinger

Sinteff

Morlet

et al. 2023

Preprint

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Proteins containing a RNB domain, originally identified in E. coli RNase II, are widely present throughout the tree of life. Many RNB proteins are endowed with 3'-5' exoribonucleolytic activity but some have lost catalytic function during evolution. Database searches identified a new RNB domain containing protein in human: HELZ2. Analysis of genomic and expression data with evolutionary information suggested that the human HELZ2 protein is produced from an unforeseen non-canonical initiation codon in Hominidae. This unusual property was confirmed experimentally, extending the human protein by 247 residues. Human HELZ2 was further shown to be an active ribonuclease despite the substitution of a key residue in its catalytic center. HELZ2 harbors also two RNA helicase domains and several zinc-fingers and its expression is induced by interferon treatment. We demonstrate that HELZ2 is able to degrade structured RNAs through the coordinated ATP-dependent displacement of duplex RNA mediated by its RNA helicase domains and its 3'-5' ribonucleolytic action. The expression characteristics and biochemical properties of HELZ2 support a role for this factor in response to viruses and/or mobile elements.

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Section: Discussionmentioning

confidence: 99%

HELZ2: a new, interferon-regulated, human 3’-5’ exoribonuclease of the RNB family is expressed from a non-canonical initiation codon

Huntzinger

Sinteff

Morlet

et al. 2023

Preprint

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“…Interestingly, the most upregulated DEPs proteins in PPM1D +/tr microglia are several regulators of ubiquitin signaling and innate immune pathways (Table 6). These included, CDC34, a Cullin-Ring E2 ubiquitin-conjugating enzyme, GBP5, a member of the GTPase subfamily induced by interferon-gamma (IFN-γ), CDBP2, a CD2 antigen cytoplasmic tail-binding protein that regulates T-cell activation and IL-2 production, KLHDC4, a member of the Kelch-like proteins that act as substrate adaptors for Cullin 3 ubiquitin ligases, PELI1, an E3 ubiquitinprotein ligase pellino homolog that regulates NLRP3-induced caspase-1 activation and IL-1β maturation, ZNFX1, which functions as a dsRNA sensor and regulator of antiviral responses, and TEP1, a telomerase protein component that can influence innate immune responses through cGAS/STING (cyclic GMP-AMP synthase-stimulator of interferon genes) activation, a cytosolic DNA sensor (86)(87)(88)(89)(90)(91)(92).…”

Section: Proteomics: Microgliamentioning

confidence: 99%

Proteomics and phosphoproteomics profiling in glutamatergic neurons and microglia in an iPSC model of Jansen de Vries Syndrome

Aguilan,

Pedrosa,

Dolstra

et al. 2023

Preprint

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Background: Jansen de Vries Syndrome (JdVS) is a rare neurodevelopmental disorder (NDD) caused by gain-of-function (GOF) truncating mutations in PPM1D exons 5 or 6. PPM1D is a serine/threonine phosphatase that plays an important role in the DNA damage response (DDR) by negatively regulating TP53 (P53). JdVS-associated mutations lead to the formation of a truncated PPM1D protein that retains catalytic activity and has a GOF effect because of reduced degradation. Somatic PPM1D exons 5 and 6 truncating mutations are well-established factors in a number of cancers, due to excessive dephosphorylation and reduced function of P53 and other substrates involved in DDR. Children with JdVS have a variety of neurodevelopmental, psychiatric, and physical problems. In addition, a small fraction has acute neuropsychiatric decompensation apparently triggered by infection or severe non-infectious environmental stress factors. Methods: To understand the molecular basis of JdVS, we developed an induced pluripotent stem cell (iPSC) model system. iPSCs heterozygous for the truncating variant (PPM1D+/tr), were made from a patient, and control lines engineered using CRISPR-Cas9 gene editing. Proteomics and phosphoprotemics analyses were carried out on iPSC-derived glutamatergic neurons and microglia from three control and three PPM1D+/tr iPSC lines. We also analyzed the effect of the TLR4 agonist, lipopolysaccharide, to understand how activation of the innate immune system in microglia could account for acute behavioral decompensation. Results: One of the major findings was the downregulation of POGZ in unstimulated microglia. Since loss-of-function variants in the POGZ gene are well-known causes of autism spectrum disorder, the decrease in PPM1D+/tr microglia suggests this plays a role in the neurodevelopmental aspects of JdVS. In addition, neurons, baseline, and LPS-stimulated microglia show marked alterations in the expression of several E3 ubiquitin ligases, most notably UBR4, and regulators of innate immunity, chromatin structure, ErbB signaling, and splicing. In addition, pathway analysis points to overlap with neurodegenerative disorders. Limitations: Owing to the cost and labor-intensive nature of iPSC research, the sample size was small. Conclusions: Our findings provide insight into the molecular basis of JdVS and can be extrapolated to understand neuropsychiatric decompensation that occurs in subgroups of patients with ASD and other NDDs.

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“…Among these are specific DExD/H-box helicases known to play a role in the immune response of vertebrates, including DDX1 (LOC101857175), DDX41(LOC101864496), DHX9 (LOC101848799), and DHX15 (LOC101860724). Furthermore, the Aplysia genome contains In parallel to RIG-I and DExD/H-box helicases, zinc finger NFX1-type containing 1 (ZNFX1), has also been implicated as a dsRNA sensor and antiviral protein in metazoans [31]. Using conserved domains, PANTHER annotation from IPS (PTHR10887:SF470), and homology search, three potential ZNFX1 genes (LOC101862822, LOC101857249, LOC101851452) were identified.…”

Section: Nucleotide Receptorsmentioning

confidence: 99%

In search of the Aplysia immunome: an in silico study

Kron

2022

BMC Genomics

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The immune repertoires of mollusks beyond commercially important organisms such as the pacific oyster Crassostrea gigas or vectors for human pathogens like the bloodfluke planorb Biomphalaria glabrata are understudied. Despite being an important model for neural aging and the role of inflammation in neuropathic pain, the immune repertoire of Aplysia californica is poorly understood. Recent discovery of a neurotropic nidovirus in Aplysia has highlighted the need for a better understanding of the Aplysia immunome. To address this gap in the literature, the Aplysia reference genome was mined using InterProScan and OrthoFinder for putative immune genes. The Aplysia genome encodes orthologs of all critical components of the classical Toll-like receptor (TLR) signaling pathway. The presence of many more TLRs and TLR associated adapters than known from vertebrates suggest yet uncharacterized, novel TLR associated signaling pathways. Aplysia also retains many nucleotide receptors and antiviral effectors known to play a key role in viral defense in vertebrates. However, the absence of key antiviral signaling adapters MAVS and STING in the Aplysia genome suggests divergence from vertebrates and bivalves in these pathways. The resulting immune gene set of this in silico study provides a basis for interpretation of future immune studies in this important model organism.

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A glimpse on metazoan ZNFX1 helicases, ancient players of antiviral innate immunity

Cited by 7 publications

References 95 publications

HELZ2: a new, interferon-regulated, human 3’-5’ exoribonuclease of the RNB family is expressed from a non-canonical initiation codon

HELZ2: a new, interferon-regulated, human 3’-5’ exoribonuclease of the RNB family is expressed from a non-canonical initiation codon

Proteomics and phosphoproteomics profiling in glutamatergic neurons and microglia in an iPSC model of Jansen de Vries Syndrome

In search of the Aplysia immunome: an in silico study

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