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LARP4 Is an RNA-Binding Protein That Binds Nuclear-Encoded Mitochondrial mRNAs To Promote Mitochondrial Function

ABSTRACT: Mitochondrial associated RNA-binding proteins (RBPs) have emerged as key contributors to mitochondrial biogenesis and homeostasis. With few examples described, we set out to identify RBPs that post-transcriptionally regulate nuclear-encoded mitochondrial mRNAs (NEMmRNAs). Our analysis of RNA-target sets of RBPs made available by ENCODE identified several RBPs with a preference for binding NEMmRNAs, of which we selected LARP4, a La RBP family member, for further study. We show that LARP4’s RNA-target set is particularly enriched in mRNAs that encode for respiratory chain complex proteins (RCCPs) and mitochondrial ribosome proteins (MRPs) across multiple human cell lines. CRISPR knockout cells in conjunction with quantitative proteomics show that protein levels of RCCPs and MRPs are significantly reduced upon loss of LARP4. Furthermore, we show that LARP4 depletion reduces mitochondrial function, and this phenotype is ameliorated by LARP4 re-expression. Our findings shed light onto a novel function for LARP4 as an RBP that binds to NEMmRNAs to promote mitochondrial respiratory function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE193134 | GEO | 2024/03/11

REPOSITORIES: GEO

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LARP4 Is an RNA-Binding Protein That Binds Nuclear-Encoded Mitochondrial mRNAs To Promote Mitochondrial Function

Project description:Mitochondria-associated RNA-binding proteins have emerged as key contributors to mitochondrial biogenesis and homeostasis. With few examples known, we set out to identify RBPs that regulate nuclear-encoded mitochondrial mRNAs. Our systematic analysis of RNA targets of 150 RBPs identified RBPs with a preference for binding NEM mRNAs, including LARP4, a La RBP family member. We show that LARP4s targets are particularly enriched in mRNAs that encode respiratory chain complex proteins and mitochondrial ribosome proteins across multiple human cell lines. Through quantitative proteomics, we demonstrate that depletion of LARP4 leads to a significant reduction in RCCP and MRP protein levels. Furthermore, we show that LARP4 depletion reduces mitochondrial function, and that LARP4 re-expression rescues this phenotype. Our findings shed light on a novel function for LARP4 as an RBP that binds to and positively regulates NEM mRNAs to promote mitochondrial respiratory function.

2023-11-08 | MSV000093340 | MassIVE

rec-Y2H matrix in S. cerevisiae screening reveals a vast potential for direct protein-protein interactions among RNA binding proteins

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2021-09-01 | E-MTAB-9612 | biostudies-arrayexpress

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Balancing of mitochondrial translation through METTL8-mediated m3C modification of mitochondrial tRNAs

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Project description:The mechanisms of RNA-binding proteins (RBPs)-mediated post-transcriptional regulation of pre-existing mRNAs, which is essential for spermatogenesis, remains poorly understood. Here, we identify a germline-specific mitochondrial RBP AMG-1, a homolog of mammalian LRPPRC, required for spermatogenesis in C. elegans. amg-1 mutation hinders germline development without affecting somatic development and leads to the aberrant mitochondrial morphology and structure associated with mitochondrial dysfunctions specifically in germline. We demonstrate that AMG-1 is most frequently bound to mtDNA-encoded 12S and 16S ribosomal RNA, the essential components of mitochondrial ribosome, and that 12S rRNA expression mediated by AMG-1 is crucial for germline mitochondrial protein homeostasis. Besides, mitochondrial dysfunction by AMG-1 mutation triggers sperm apoptosis in C. elegans. Furthermore, SLRP-1, the homolog of mammalian SLIRP in C. elegans, interacts with AMG-1 genetically to regulate germline development and reproductive success in C. elegans. Taken together, these findings reveal the novel function of mtRBP in specifically regulating germline development.

2023-01-16 | GSE222138 | GEO

RNA-binding protein complex AMG-1/SLRP-1 mediates germline development and spermatogenesis by maintaining mitochondrial homeostasis in Caenorhabditis elegans [RNA-seq]

2023-01-16 | GSE222137 | GEO

RNase-mediated protein footprint sequencing reveals protein-binding sites throughout the human transcriptome

Project description:RNAs are continuously associated with RNA-binding proteins (RBPs), and these interactions are necessary for many key cellular processes ranging from splicing to chromatin regulation. Although numerous approaches have been developed to map RNA-binding sites of individual RBPs, few methods exist that allow assessment of global RBP-RNA interactions. Here, we describe a universal, high-throughput, ribonuclease-mediated protein footprint sequencing approach that reveals RNA-protein interaction sites throughout a transcriptome of interest. We apply this method to the HeLa transcriptome and compare RBP binding sites found using different cross-linkers and ribonucleases. From this analysis, we identify numerous putative RBP binding motifs, reveal novel insights into co-binding by RBPs, and uncover a significant enrichment for disease-associated polymorphisms within RBP interaction sites. Protein interaction profile sequencing (PIP-seq) in HeLa cells. Two crosslinkers (formaldehyde and UV) with two RNases (dsRNase and ssRNase) each, as well as a no-crosslink sample. Performed with and without proteins. Three replicates for formaldehyde, two replicates for UV, single replicate for no crosslinker.

2013-11-06 | E-GEOD-49309 | biostudies-arrayexpress

C6orf203 is an RNA-binding protein involved in mitochondrial protein synthesis

Project description:In all biological systems, RNAs are associated with RNA-binding proteins (RBPs), forming complexes that control gene regulatory mechanisms, from RNA synthesis to decay. In mammalian mitochondria, post-transcriptional regulation of gene expression is conducted by mitochondrial RBPs (mt-RBPs) at various stages of mt-RNA metabolism, including polycistronic transcript production, its processing into individual transcripts, mt-RNA modifications, stability, translation, and degradation. To date, only a handful of mt-RBPs have been characterized. Here, we describe a putative human mitochondrial protein, C6orf203, that contains an S4-like domain - an evolutionarily conserved RNA-binding domain previously identified in proteins involved in translation. Our data show C6orf203 to bind highly-structured RNA in vitro and associate with the mitoribosomal large subunit in HEK293T cells. Knockout of C6orf203 leads to a decrease in mitochondrial translation and consequent OXPHOS deficiency, without affecting mitochondrial RNA levels. Although mitoribosome stability is not affected in C6orf203-depleted cells, mitoribosome profiling analysis revealed a global disruption of the association of mt-mRNAs with the mitoribosome, suggesting that C6orf203 may be required for the proper maturation and functioning of the mitoribosome. We therefore propose C6orf203 to be a novel RNA-binding protein involved in mitochondrial translation, expanding the repertoire of factors engaged in this process.

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Project description:Quantitative criteria to identify proteins as RNA-binding proteins (RBPs) are presently lacking, as are criteria to define RBP target RNAs. Here, we develop an ultraviolet (UV) cross-linking immunoprecipitation (CLIP)-sequencing method, easyCLIP. easyCLIP provides absolute cross-link rates, as well as increased simplicity, efficiency, and capacity to visualize RNA libraries. Measurement of >200 independent cross-link experiments across >35 proteins identifies an RNA cross-link rate threshold that distinguishes RBPs from non-RBPs and defines target RNAs as those with a complex frequency unlikely for a random protein. We apply easyCLIP to the 33 most recurrent cancer mutations across 28 RBPs, finding increased RNA binding per RBP molecule for PCBP1 L100P/Q cancer mutations. Quantitating RBP-RNA interactions can thus nominate proteins as RBPs and define the impact of specific disease-associated RBP mutations on RNA association.

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