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Makorin 1 controls embryonic patterning by alleviating Bruno1-mediated repression of oskar translation

ABSTRACT: Makorins are evolutionary conserved proteins that contain C3H-type zinc finger modules and a RING E3 ubiquitin ligase domain. In Drosophila maternal Makorin 1 (Mkrn1) has been linked to embryonic patterning but the mechanism remained unsolved. Here, we show that Mkrn1 is essential for axis specification and pole plasm assembly by translational activation of oskar. We demonstrate that Mkrn1 interacts with poly(A) binding protein (pAbp) and binds specifically to osk 3’ UTR in regions overlapping Bruno1 (Bru1) responsive elements (BREs), which regulate osk translation. We observe increased association of the translational repressor Bru1 with osk mRNA upon depletion of Mkrn1, indicating that both proteins compete for osk binding. Consistently, reducing Bru1 dosage partially rescues viability and Osk protein level in ovaries from Mkrn1 females. We conclude that Mkrn1 controls embryonic patterning and germ cell formation by specifically activating osk translation, most likely by competing with Bru1 to bind to osk 3’ UTR.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE139030 | GEO | 2022/10/17

REPOSITORIES: GEO

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Makorin 1 controls embryonic patterning by alleviating Bruno1-mediated repression of oskar translation

Project description:Makorins are evolutionary conserved proteins that contain C3H-type zinc finger modules and a RING E3 ubiquitin ligase domain. In Drosophila maternal Makorin 1 (Mkrn1) has been linked to embryonic patterning but the mechanism remained unsolved. Here, we show that Mkrn1 is essential for axis specification and pole plasm assembly by translational activation of oskar (osk). We demonstrate that Mkrn1 interacts with poly(A) binding protein (pAbp) and binds specifically to osk 3’ UTR in regions overlapping with Bruno1 (Bru1) responsive elements (BREs) that regulate osk translation. We observe increased association of the translational repressor Bru1 with osk mRNA upon depletion of Mkrn1, indicating that both proteins compete for osk binding. Consistently, reducing Bru1 dosage partially rescues viability and Osk protein level in ovaries from Mkrn1 females. We conclude that Mkrn1 controls embryonic patterning and germ cell formation by specifically activating osk translation, most likely by competing with Bru1 to bind to osk 3’ UTR.

2020-01-06 | GSE123052 | GEO

Makorin 1 controls embryonic patterning by alleviating Bruno-mediated repression of oskar translation

Project description:Makorins are an evolutionary conserved family of proteins that contain C3H-type zinc finger modules and a RING E3 ubiquitin ligase domain. Previous analysis indicated a maternal role for Makorin 1 (Mkrn1) in Drosophila embryonic patterning and germ cell specification, but the underlying mechanism has remained elusive. Here, we show that Mkrn1 is specifically required for translational activation of oskar, which encodes a critical regulator of axis specification and germ plasm assembly. We demonstrate that Mkrn1 interacts with poly(A) binding protein (pAbp) and specifically binds osk 3’ UTR adjacent to A-rich sequences. The binding of Mkrn1 to osk 3’UTR occurs in a region that overlaps with Bruno responsive elements (BRE), previously shown to have a dual role in regulating osk translation. We observe an increased association of the translational repressor Bruno (Bru) with osk mRNA upon depletion of Mkrn1, implying that both proteins compete with each other for osk binding. Consistently, reducing Bru dosage is sufficient to partially rescue osk translation and the embryonic lethality associated with Mkrn1 alteration. Thus, we conclude that Mkrn1 controls embryonic patterning and germ cell formation by specifically activating osk translation via displacing Bru from its 3’ UTR

2020-01-29 | PXD011802 | Pride

The RNA-binding ubiquitin ligase MKRN1 functions in ribosome-associated quality control of poly(A)-translation

Project description:Human cells have evolved quality control mechanisms to ensure protein homeostasis by detecting and degrading aberrant mRNAs and protein products. A common source of aberrant mRNAs is premature polyadenylation, which can result in non-functional protein products. Translating ribosomes that encounter poly(A) sequences are terminally stalled, followed by ribosome recycling and rapid decay of the truncated nascent polypeptide via the ribosome-associated quality control (RQC). Here, we demonstrate that the conserved RNA-binding E3 ubiquitin ligase Makorin Ring Finger Protein 1 (MKRN1) promotes ribosome stalling at continuous A-tracts during RQC. Using individual-nucleotide resolution UV crosslinking and immunoprecipitation (iCLIP), we show that MKRN1 is positioned upstream of A-rich stretches and poly(A) tails in mRNAs through an interaction with the cytoplasmic poly(A)-binding protein (PABP). Ubiquitin remnant profiling uncovered PABP and ribosomal protein RPS10 as well as additional translational regulators as main substrates of MRKN1. We propose that MKRN1 serves as a first line of poly(A) recognition at the mRNA level to prevent production of erroneous proteins, thus maintaining proteome integrity.

2019-08-19 | GSE122869 | GEO

The RNA-binding ubiquitin ligase MKRN1 acts as a sensor for ribosome-associated quality control of poly(A)-translation

Project description:Human cells have evolved multiple quality control mechanisms to ensure protein homeostasis by detecting aberrant mRNAs and protein products which are condemned for rapid decay. Translating ribosomes that run into poly(A) tails are terminally stalled, followed by ribosome recycling and rapid decay of the truncated nascent polypeptide via the ribosome-associated quality control (RQC). Here, we demonstrate that the conserved RNA-binding E3 ubiquitin ligase Makorin Ring Finger Protein 1 (MKRN1) acts as a novel sensor of poly(A) sequences to initiate ribosome stalling in RQC. Using individual-nucleotide resolution UV crosslinking and immunoprecipitation (iCLIP), we show that MKRN1 is positioned upstream of A-rich stretches and poly(A) tails in mRNAs via interaction with the cytoplasmic poly(A)-binding protein (PABP). Ubiquitin remnant profiling uncovers PABP and ribosomal protein RPS10 as well as multiple translational regulators as main targets of MRKN1-mediated ubiquitylation. The modified lysine in RPS10 is distinct from the main target sites of ZNF598, the second E3 ubiquitin ligase involved in initial ribosome stalling, indicating that multiple modifications need to converge to prevent promiscuous ubiquitylation of lysine-translating ribosomes. We propose that MKRN1 serves as a first line of poly(A) recognition at the RNA level to prevent erroneous protein products and maintain proteome integrity.

2019-08-19 | PXD011772 | Pride

Makorin 1 controls embryonic patterning by alleviating Bruno1-mediated repression of oskar translation

Project description:Makorin 1 controls embryonic patterning by alleviating Bruno1-mediated repression of oskar translation

| PRJNA507419 | ENA

Integrative genomics positions MKRN1 as a novel ribonucleoprotein within the embryonic stem cell gene regulatory network [RIP-chip]

Project description:In embryonic stem cell (ESCs), gene regulatory networks (GRNs) coordinate gene expression to maintain ESC identity; however, the complete repertoire of factors that regulate the ESC state are not fully understood. Our previous temporal microarray analysis of ESC commitment identified the E3 Ubiquitin Ligase Protein Makorin-1 (MKRN1) as a potential novel component of the ESC GRN. Here, using multilayered systems-level analyses we compiled a MKRN1-centered interactome in undifferentiated ESCs at the proteomic and ribonomic level. Proteomic analyses revealed that MKRN1 is a novel RNA-binding protein that exists within messenger ribonucleoprotein (mRNP) complexes in undifferentiated ESC populations. In accordance with its presence in mRNPs, MKRN1 is mobilized to stress granules (SG) upon arsenite-induced stress, yet MKRN1 is not required for SG formation. RIP-chip analysis revealed that MKRN1 associates with mRNAs encoding functionally related regulatory proteins involved in diverse processes such as cell differentiation, apoptosis, or secreted proteins. Thus, our unbiased systems level analyses supports a role for MKRN1 as a novel RNA-binding protein and a potential gene regulatory protein within the ESC GRN.

2015-07-15 | GSE59393 | GEO

Integrative genomics positions MKRN1 as a novel ribonucleoprotein within the embryonic stem cell gene regulatory network [expression]

2015-07-15 | GSE59392 | GEO

Cap-proximal nucleotides via differential eIF4E binding and alternative promoter usage mediate translational response to energy stress

Project description:Transcription and translation are highly energy consuming processes and both are modulated by the intracellular energy status. Transcription start site (TSS) selection and alternative promoter (AP) usage contribute to the complexity of gene expression but little is known about their impact on translation in response to metabolic deficiencies. Here we performed TSS mapping of the translatome following energy stress. We assessed the contribution of cap-proximal TSS nucleotides and strikingly found dramatic effect on translation only upon stress. As eIF4E levels were reduced, we analyzed its binding to capped-RNAs with different initiating nucleotides and found differential affinity, the lowest being for 5’cytidine, in correlation with the translational response. In addition the number of differentially translated APs was highly elevated following energy stress, suggesting that AP usage is central to the stress response. These include novel glucose-starvation-induced downstream promoters for the translation regulators eIF4A and Pabp which are translationally-induced despite the general translational inhibition. The resultant eIF4A protein is N-terminally truncated and acts as eIF4A inhibitor. The induced Pabp isoform has shorter 5'UTR removing an auto-inhibitory element. These findings uncovered several levels of coordination of transcription and translation responses to energy stress.

2017-01-25 | GSE93981 | GEO

PABP stabilizes select mRNAs populations in human cells

Project description:Gene expression is tightly regulated at the levels of both mRNA translation and stability. The poly(A) binding protein (PABP) plays a role in regulating these processes by binding the mRNA 3´ poly(A) tail and interfacing with both the translation initiation and mRNA deadenylation machineries. Here we directly investigate the impact of PABP on the translation and stability of endogenous mRNAs in human cell lines. Remarkably, our transcriptome-wide analysis does not generally detect changes to mRNA translation in PABP-depleted cells. In contrast, rapidly depleting PABP alters transcriptome abundance and stability, albeit non-uniformly. Transcripts with long half-lives and short 3’UTRs are preferentially depleted in PABP-depleted cells. PABP depletion induces cell death; however, disrupting the mRNA decapping and 5’-3’ decay machinery can partially suppress this lethality. Finally, we show that disrupting the LSM1-7 complex prevents the premature decay of mRNAs that are destabilized in PABP-depleted cells. Taken together, these findings suggest that PABP plays an important role in preventing the untimely decay of select mRNA populations in human cells.

2021-12-31 | GSE187450 | GEO

SF3B1 deficiency impairs human erythropoiesis via activation of p53 pathway: implications for understanding of ineffective erythropoiesis in MDS

Project description:SF3B1 knockdown in human CD34+ cells leads to increased apoptosis and cell cycle arrest of early-stage erythroid cells and generation of abnormally nucleated late-stage erythroblasts. RNA-seq analysis of SF3B1-knockdown erythroid progenitor CFU-E cells revealed altered splicing of an E3 ligase Makorin Ring Finger Protein 1 (MKRN1) and subsequent activation of p53 pathway.Decreased expression of genes involved in mitosis/cytokinesis pathway including polo-like kinase 1 (PLK1) was noted in SF3B1-knockdown polychromatic and orthochromatic erythroblasts comparing to control cells.

2021-04-24 | GSE173232 | GEO

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