The ubiquitin ligase Hecw controls oogenesis and neuronal homeostasis by promoting the liquid state of ribonucleoprotein particles

Specialised ribonucleoprotein (RNP) granules are a hallmark of germ cells. Among their main function is the spatial and temporal modulation of the activity of specific mRNA transcripts that allow specification of primary embryonic axes. While RNPs composition and role are well established, their regulation is poorly defined. Here, we demonstrate that Hecw, a newly identified Drosophila ubiquitin ligase, is a key modulator of RNPs in oogenesis. Loss of Hecw activity results in the formation of enlarged granules that transition from a liquid to a gel-like state. At the molecular level, Hecw depletion leads to reduced ubiquitination and activity of the translational repressor Fmrp, resulting in premature Orb expression/recruitment in nurse cells. In addition to defective oogenesis, flies lacking Hecw show neurodegenerative traits with premature aging and climbing defects due to neuronal loss that are linked to RNPs condensation. Our findings reveal an unprecedented function of ubiquitin in modulating RNP fluidity and activity.

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Hecw controls oogenesis and neuronal homeostasis by promoting the liquid state of ribonucleoprotein particles

Nature Communications ◽

10.1038/s41467-021-25809-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Valentina Fajner ◽

Fabio Giavazzi ◽

Simona Sala ◽

Amanda Oldani ◽

Emanuele Martini ◽

...

Keyword(s):

Molecular Level ◽

Neuronal Loss ◽

Premature Aging ◽

Temporal Modulation ◽

Embryonic Axes ◽

Translational Repressor ◽

Neuronal Homeostasis ◽

Rnp Granules ◽

Repressor Activity ◽

Specific Mrna

AbstractSpecialised ribonucleoprotein (RNP) granules are a hallmark of polarized cells, like neurons and germ cells. Among their main functions is the spatial and temporal modulation of the activity of specific mRNA transcripts that allow specification of primary embryonic axes. While RNPs composition and role are well established, their regulation is poorly defined. Here, we demonstrate that Hecw, a newly identified Drosophila ubiquitin ligase, is a key modulator of RNPs in oogenesis and neurons. Hecw depletion leads to the formation of enlarged granules that transition from a liquid to a gel-like state. Loss of Hecw activity results in defective oogenesis, premature aging and climbing defects associated with neuronal loss. At the molecular level, reduced ubiquitination of the Fmrp impairs its translational repressor activity, resulting in altered Orb expression in nurse cells and Profilin in neurons.

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Strategies for the Identification of Novel Brain Specific Genes Affected in Alzheimer Disease

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100029814 ◽

1989 ◽

Vol 16 (S4) ◽

pp. 483-489 ◽

Cited By ~ 7

Author(s):

D.G. Walker ◽

B.E. Boyes ◽

P.L. McGeer ◽

E.G. McGeer

Keyword(s):

Alzheimer Disease ◽

Normal Cell ◽

Temporal Cortex ◽

Neuronal Loss ◽

Brain Regions ◽

Neuritic Plaques ◽

Substantia Innominata ◽

Expression Of Genes ◽

Preliminary Description ◽

Specific Mrna

ABSTRACT:The pathological changes that occur in Alzheimer disease (AD) brain lead to a large loss of various classes of neurons and the production of novel proteinaceous elements such as neuritic plaques and neurofibrillary tangles. For the neuronal loss to occur and these elements to arise, there must be a disturbance in the expression or regulation of genes that code for proteins required for normal cell maintenance, or perhaps even for the expression of genes unique to AD. We describe the construction of a cDNA library from the human substantia innominata and strategies for isolating genes that are expressed differentially between brain regions and which may be affected by AD. Some of the results obtained using these strategies and a preliminary description of a novel brain specific mRNA of 15.5kb, whose expression is increased in AD affected temporal cortex, are presented.

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Characterization of a maturation-specific mRNA in dry mung bean embryonic axes

Planta ◽

10.1007/bf00384558 ◽

1980 ◽

Vol 149 (3) ◽

pp. 227-233 ◽

Cited By ~ 16

Author(s):

Albert R. Carlier ◽

A. Manickam ◽

Willy J. Peumans

Keyword(s):

Mung Bean ◽

Embryonic Axes ◽

Specific Mrna

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Unraveling the Pathways to Neuronal Homeostasis and Disease: Mechanistic Insights into the Role of RNA-Binding Proteins and Associated Factors

International Journal of Molecular Sciences ◽

10.3390/ijms19082280 ◽

2018 ◽

Vol 19 (8) ◽

pp. 2280 ◽

Cited By ~ 17

Author(s):

Stylianos Ravanidis ◽

Fedon-Giasin Kattan ◽

Epaminondas Doxakis

Keyword(s):

Associated Factors ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Muscular Atrophy ◽

Fragile X ◽

Autism Spectrum ◽

Cytoplasmic Inclusions ◽

Neuronal Homeostasis ◽

Rnp Granules

The timing, dosage and location of gene expression are fundamental determinants of brain architectural complexity. In neurons, this is, primarily, achieved by specific sets of trans-acting RNA-binding proteins (RBPs) and their associated factors that bind to specific cis elements throughout the RNA sequence to regulate splicing, polyadenylation, stability, transport and localized translation at both axons and dendrites. Not surprisingly, misregulation of RBP expression or disruption of its function due to mutations or sequestration into nuclear or cytoplasmic inclusions have been linked to the pathogenesis of several neuropsychiatric and neurodegenerative disorders such as fragile-X syndrome, autism spectrum disorders, spinal muscular atrophy, amyotrophic lateral sclerosis and frontotemporal dementia. This review discusses the roles of Pumilio, Staufen, IGF2BP, FMRP, Sam68, CPEB, NOVA, ELAVL, SMN, TDP43, FUS, TAF15, and TIA1/TIAR in RNA metabolism by analyzing their specific molecular and cellular function, the neurological symptoms associated with their perturbation, and their axodendritic transport/localization along with their target mRNAs as part of larger macromolecular complexes termed ribonucleoprotein (RNP) granules.

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Novel players fine-tune plant trade-offs

Essays in Biochemistry ◽

10.1042/bse0580083 ◽

2015 ◽

Vol 58 ◽

pp. 83-100 ◽

Cited By ~ 25

Author(s):

Selena Gimenez-Ibanez ◽

Marta Boter ◽

Roberto Solano

Keyword(s):

Ubiquitin Ligase ◽

Feedback Loop ◽

Molecular Level ◽

26S Proteasome ◽

Signalling Molecules ◽

Transcriptional Reprogramming ◽

Trade Offs ◽

Jaz Proteins ◽

Regulatory Feedback Loop ◽

Fine Tune

Jasmonates (JAs) are essential signalling molecules that co-ordinate the plant response to biotic and abiotic challenges, as well as co-ordinating several developmental processes. Huge progress has been made over the last decade in understanding the components and mechanisms that govern JA perception and signalling. The bioactive form of the hormone, (+)-7-iso-jasmonyl-l-isoleucine (JA-Ile), is perceived by the COI1–JAZ co-receptor complex. JASMONATE ZIM DOMAIN (JAZ) proteins also act as direct repressors of transcriptional activators such as MYC2. In the emerging picture of JA-Ile perception and signalling, COI1 operates as an E3 ubiquitin ligase that upon binding of JA-Ile targets JAZ repressors for degradation by the 26S proteasome, thereby derepressing transcription factors such as MYC2, which in turn activate JA-Ile-dependent transcriptional reprogramming. It is noteworthy that MYCs and different spliced variants of the JAZ proteins are involved in a negative regulatory feedback loop, which suggests a model that rapidly turns the transcriptional JA-Ile responses on and off and thereby avoids a detrimental overactivation of the pathway. This chapter highlights the most recent advances in our understanding of JA-Ile signalling, focusing on the latest repertoire of new targets of JAZ proteins to control different sets of JA-Ile-mediated responses, novel mechanisms of negative regulation of JA-Ile signalling, and hormonal cross-talk at the molecular level that ultimately determines plant adaptability and survival.

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