BackgroundTribbles proteins are conserved pseudokinases that function to control kinase signalling and transcription in diverse biological processes. Abnormal function in human Tribbles has been implicated in a number of diseases including leukaemia, metabolic syndromes and cardiovascular diseases. Caenorhabditis elegans Tribbles NIPI-3 was previously shown to activate host defense upon infection by promoting the conserved PMK-1/p38 mitogen-activated protein kinase (MAPK) signalling pathway. Despite the prominent role of Tribbles proteins in many species, our knowledge of their mechanism of action is fragmented, and the in vivo functional relevance of their interactions with other proteins remains largely unknown.ResultsHere, by characterizing nipi-3 null mutants, we show that nipi-3 is essential for larval development and viability. Through analyses of genetic suppressors of nipi-3 null mutant lethality, we show that NIPI-3 negatively controls PMK-1/p38 signalling via transcriptional repression of the C/EBP transcription factor CEBP-1. We identified CEBP-1’s transcriptional targets by ChIP-seq analyses and found them to be enriched in genes involved in development and stress responses. Unlike its cell-autonomous role in innate immunity, NIPI-3 is required in multiple tissues to control organismal development.ConclusionsTogether, our data uncover an unprecedented crosstalk involving multiple tissues, in which NIPI-3 acts as a master regulator to inhibit CEBP-1 and the PMK-1/p38 MAPK pathway. In doing so, it keeps innate immunity in check and ensures proper organismal development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-016-0320-z) contains supplementary material, which is available to authorized users.
The mechanisms underlying axon regeneration in mature neurons are relevant to the understanding of normal nervous system maintenance and for developing therapeutic strategies for injury. Here, we report novel pathways in axon regeneration, identified by extending our previous function-based screen using the C. elegans mechanosensory neuron axotomy model. We identify an unexpected role of the nicotinamide adenine dinucleotide (NAD+) synthesizing enzyme, NMAT-2/NMNAT, in axon regeneration. NMAT-2 inhibits axon regrowth via cell-autonomous and non-autonomous mechanisms. NMAT-2 enzymatic activity is required to repress regrowth. Further, we find differential requirements for proteins in membrane contact site, components and regulators of the extracellular matrix, membrane trafficking, microtubule and actin cytoskeleton, the conserved Kelch-domain protein IVNS-1, and the orphan transporter MFSD-6 in axon regrowth. Identification of these new pathways expands our understanding of the molecular basis of axonal injury response and regeneration.
The nervous system plays critical roles in the stress response. Animals can survive and function under harsh conditions, and resist and recover from injuries because neurons perceive and respond to various stressors through specific regulatory mechanisms. Caenorhabditis elegans has served as an excellent model to discover fundamental mechanisms underlying the neuronal response to stress. The basic physiological processes that C. elegans exhibits under stress conditions are similar to those observed in higher organisms. Many molecular pathways activated by environmental and cellular stresses are also conserved. In this review, we summarize major findings in examining neuronal responses to hypoxia, oxidative stress, osmotic stress, and traumatic injury. These studies from C. elegans have provided novel insights into our understanding of neuronal responses to stress at the molecular, cellular, and circuit levels.
The basic leucine-zipper (bZIP) domain transcription factors CCAAT/enhancer-binding proteins (C/EBP) have a variety of roles in cell proliferation, differentiation, and stress response. In the nervous system, several isoforms of C/EBP function in learning and memory, neuronal plasticity, neuroinflammation, and axon regeneration. We previously reported that the Caenorhabditis elegans C/EBP homolog, CEBP-1, is essential for axon regeneration. CEBP-1 consists of 319 amino acids, with its bZIP domain at the C-terminus and a long N-terminal fragment with no known protein motifs. Here, using forward genetic screening with targeted genome editing, we have identified a unique domain in the N-terminus that is critical for its in vivo function. Additionally, we characterized three nuclear localization signals (NLS) in CEBP-1 that act together to mediate CEBP-1’s nuclear import. Moreover, the Importin-α, IMA-3, can bind to CEBP-1 via one of the NLS. ima-3 is ubiquitously expressed in all somatic cells, and ima-3 null mutants are larval lethal. Using Cre-lox dependent neuron-specific deletion strategy, we show that ima-3 is not critical for axon development, but is required for axon regeneration in adults. Together, these data advance our understanding of CEBP-1’s function, and suggest new regulators that remain to be identified to expand the CEBP-1 protein interactome.
The 3′ untranslated regions (3′ UTRs) of mRNAs mediate post-transcriptional regulation of genes in many biological processes. Cis elements in 3′ UTRs can interact with RNA-binding factors in sequence-specific or structure-dependent manners, enabling regulation of mRNA stability, translation, and localization. Caenorhabditis elegans CEBP-1 is a conserved transcription factor of the C/EBP family, and functions in diverse contexts, from neuronal development and axon regeneration to organismal growth. Previous studies revealed that the levels of cebp-1 mRNA in neurons depend on its 3′ UTR and are also negatively regulated by the E3 ubiquitin ligase RPM-1. Here, by systematically dissecting cebp-1’s 3′ UTR, we test the roles of specific cis elements in cebp-1 expression and function in neurons. We present evidence for a putative stem-loop in the cebp-1 3′ UTR that contributes to basal expression levels of mRNA and to negative regulation by rpm-1. Mutant animals lacking the endogenous cebp-1 3′ UTR showed a noticeable increased expression of cebp-1 mRNA and enhanced the neuronal developmental phenotypes of rpm-1 mutants. Our data reveal multiple cis elements within cebp-1’s 3′ UTR that help to optimize CEBP-1 expression levels in neuronal development.
P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are regulatory small non-coding RNAs that participate in transposon inactivation, chromatin regulation, and endogenous gene regulation. Numerous genetic and epigenetic factors regulate cell proliferation and tumor metastasis. PIWI proteins and piRNAs have been revealed to function in regulating upstream or downstream of oncogenes or tumor-suppressor genes in cancer tissues. In the present review, we summarize major recent findings in uncovering the regulation and role of PIWI proteins and piRNAs in tumorigenesis and highlight some of the promising applications of specific piRNAs in cancer therapeutics and as cancer biomarkers.
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