Biology subjects

Pietrokovski, S.

Publications and source records attributed to Pietrokovski, S..

4 recordsLinked to original sources

bioRxiv2024

The RNA-binding protein PRRC2B preserves 5' TOP mRNA during starvation to maintain ribosome biogenesis during nutrient recovery

PRRC2B is an intrinsically disordered RNA-binding protein that is part of the cells translation machinery. Here we show that PRRC2B has two alternatively spliced mRNA transcripts producing major long and minor short isoforms. Mass spectrometry-based interaction studies indicated that both isoforms associate with the 40S ribosomal subunit and translation initiation factors. Importantly, the long isoform also interacted with additional RNA-binding proteins through its unique Arg/Gly-rich region. Among these is LARP1, a regulator of 5 terminal oligopyrimidine (TOP) mRNAs under conditions of mTOR inhibition. We discovered that like LARP1, PRRC2B is necessary for preservation of 5 TOP mRNA levels, particularly those encoding ribosomal proteins, during amino acid starvation. In its absence, the rapid de novo translation of ribosomal proteins that takes place upon nutrient recovery is impeded. Overall, our study elucidates a newly discovered function for PRRC2B as an RNA-binding protein that regulates ribosomal biogenesis upon metabolic shift, in addition to its established function in initiating translation of specific mRNA targets.

molecular biology↗

bioRxiv2024

Expanding and enriching the LncRNA gene landscape using the GeneCaRNA database

The GeneCaRNA human gene database is a member of the GeneCards Suite. It presents [~]280,000 human non-coding RNA genes, identified algorithmically from [~]690,000 RNAcentrals transcripts. This expands by [~]tenfold the ncRNA gene count relative to other sources. GeneCaRNA thus contains [~]120,000 long non-coding RNAs (LncRNAs, >200 bases long), including [~]100,000 novel genes. The latter have sparse functional information, a vast terra incognita for future research. LncRNA genes are uniformly represented on all nuclear chromosomes, with 10 genes on mitochondrial DNA. Data obtained from MalaCards, another GeneCards Suite member, finds 1,547 genes associated with 1 to 50 diseases. [~]15% of the associations portray experimental evidence, with cancers tending to be multigenic. Preliminary text mining within GeneCaRNA discovers interactions of LncRNA transcripts with target gene products, with 25% being ncRNAs and 75% proteins. GeneCaRNA has a biological pathways section, which at present shows 131 pathways for 38 LncRNA genes, a basis for future expansion. Finally, our GeneHancer database provides regulatory elements for [~]110,000 LncRNA genes, offering pointers for co-regulated genes and genetic linkages from enhancers to diseases. We anticipate that the broad vista provided by GeneCaRNA will serve as an essential guide for further LncRNA research in disease decipherment.

bioinformatics↗

bioRxiv2023

Egg MVBs elicit an antimicrobial pathway to degrade paternal mitochondria after fertilization

Mitochondria are maternally inherited, but the mechanisms underlying paternal mitochondrial elimination (PME) after fertilization are far less clear. Using Drosophila, we show that special egg-derived multivesicular bodies (MVBs) promote PME by activating LC3-associated phagocytosis (LAP), a cellular defense pathway commonly employed against invading microbes. Upon fertilization, the egg MVBs engage and densely coat the sperm flagellum, forming extended flagellum vesicular sheaths (FVSs), within which the paternal mitochondria degrade. Inactivation of multiple LAP pathway components, such as Rubicon, a LAP-specific class III PI(3)K complex protein, significantly attenuates PME. Furthermore, recruitment of Atg8/LC3 to the FVS requires both Rubicon and the Atg8/LC3 conjugation machinery. Other LAP pathway events, such as production of the phospholipid PtdIns(3)P and reactive oxygen species (ROS), also unfold during PME. Finally, we provide evidence that a similar pathway might also mediate PME in mammals, highlighting the notion that eggs may regard paternal mitochondria as potentially dangerous trespassers.

developmental biology↗

bioRxiv2023

Loss-of-function cancer-associated mutations in the EIF4G2 non-canonical translation initiation factor

Tumor cells often exploit the protein translation machinery, resulting in enhanced protein expression essential for tumor growth. Since canonical translation initiation is often suppressed due to cell stress in the tumor microenvironment, non-canonical translation initiation mechanisms become particularly important for shaping the tumor proteome. EIF4G2 is a non-canonical translation initiation factor that mediates internal ribosome entry site [IRES] and upstream open reading frame [uORF] dependent initiation mechanisms, which can be used to modulate protein expression in cancer. Here we explored the contribution of EIF4G2 to cancer by screening the COSMIC database for EIF4G2 somatic mutations in cancer patients. Functional examination of missense mutations revealed deleterious effects on EIF4G2 protein-protein interactions, and importantly, on its ability to mediate non-canonical translation initiation. Specifically, one mutation, R178Q, led to reductions in protein expression and near complete loss-of-function. Two other mutations within the MIF4G domain specifically affected EIF4G2s ability to mediate IRES-dependent translation initiation but not that of target mRNAs with uORFs. These results shed light on both the structure-function of EIF4G2 and its potential tumor suppressor effects.

cancer biology↗