Biology subjects

Molina, H.

Publications and source records attributed to Molina, H..

4 recordsLinked to original sources

bioRxiv2018

An adaptive stress-induced tRNA depletion response mediates codon-based gene repression and growth suppression

Eukaryotic transfer RNAs can become selectively fragmented upon various stresses, generating tRNA-derived small RNA fragments. Such fragmentation has been reported to impact a small fraction of the tRNA pool and thus presumed to not directly impact translation. We report that oxidative stress can rapidly generate tyrosine tRNAGUA fragments in human cells--causing significant depletion of the precursor tRNA. Tyrosine tRNAGUA depletion impaired translation of growth and metabolic genes enriched in cognate tyrosine codons. Depletion of tyrosine tRNAGUA or its translationally regulated targets USP3 and SCD repressed proliferation--revealing a dedicated tRNA-regulated growth suppressive pathway for oxidative stress response. Tyrosine fragments are generated in a DIS3L2 exoribonuclease-dependent manner and inhibit hnRNPA1-mediated transcript destabilization. Moreover, tyrosine fragmentation is conserved in C. elegans. Thus, tRNA fragmentation can coordinately generate trans-acting small-RNAs and functionally deplete a tRNA. Our findings reveal the existence of an underlying adaptive codon-based regulatory response inherent to the genetic code.

molecular biology↗

bioRxiv2018

Nuclear TARBP2 drives oncogenic dysregulation of RNA splicing and decay

Post-transcriptional regulation of RNA stability is a key step in gene expression control. We describe a regulatory program, mediated by the double-stranded RNA binding protein TARBP2, that controls RNA stability in the nucleus. TARBP2 binding to pre-mRNAs results in increased intron retention, subsequently leading to targeted degradation of TARBP2-bound transcripts. This is mediated by TARBP2 recruitment of the m6A RNA methylation machinery to its target transcripts, where deposition of m6A marks influences the recruitment of splicing regulators, inhibiting efficient splicing. Interactions between TARBP2 and the nucleoprotein TPR then promote degradation of these TARBP2-bound transcripts by the nuclear exosome. Additionally, analysis of clinical gene expression datasets revealed a functional role for this TARBP2 pathway in lung cancer. Using xenograft mouse models, we find that TARBP2 impacts tumor growth in the lung, and that this function is dependent on TARBP2-mediated destabilization of ABCA3 and FOXN3. Finally, we establish the transcription factor ZNF143 as an upstream regulator of TARBP2 expression.\n\nRESEARCH HIGHLIGHTSO_LIThe RNA-binding protein TARBP2 controls the stability of its target transcripts in the nucleus\nC_LIO_LINuclear TARBP2 recruits the methyltransferase complex to deposit m6A marks on its target transcripts\nC_LIO_LITARBP2 and m6A-mediated interactions with splicing and nuclear RNA surveillance complexes result in target transcript intron retention and decay.\nC_LIO_LIIncreased TARBP2 expression is associated with lung cancer and promotes lung cancer growth in vivo.\nC_LIO_LIThe transcription factor ZNF143 drives oncogenic TARBP2 upregulation in lung cancer.\nC_LI

molecular biology↗

bioRxiv2018

PI31 is an adaptor protein for proteasome transport in axons

Protein degradation by the ubiquitin-proteasome system (UPS) is critical for neuronal development, plasticity and function. Neurons utilize microtubule-dependent molecular motors to allocate proteasomes to synapses, but how proteasomes are coupled to motor proteins and how this transport is regulated to meet changing demand for protein breakdown remains largely unknown. We show that the conserved proteasome-binding protein PI31 serves as an adaptor to directly couple proteasomes with dynein light chain proteins (DYNLL1/2). Inactivation of PI31 inhibits proteasome motility in axons and disrupts synaptic protein homeostasis, structure and function. Moreover, phosphorylation of PI31 at a conserved site by p38 MAP kinase promotes binding to DYNLL1/2, and a non-phosphorable PI31 mutant impairs proteasome movement in axons, suggesting a mechanism to regulate loading of proteasomes onto motor proteins. Because mutations affecting PI31 activity are associated with human neurodegenerative diseases, impairment of PI31-mediated axonal transport of proteasomes may be the root cause of these disorders.

cell biology↗

bioRxiv2017

A Neuropeptide Signaling System That Rapidly Enforces Paternity In The Aedes aegypti Mosquito

Female Dengue and Zika vector mosquitoes (Aedes aegypti) generally mate once, with sperm from this male fertilizing all eggs produced in her lifetime. Here we implicate HP-I, an Aedes- and male-specific neuropeptide transferred to females, and its cognate receptor in the female, NPYLR1, in rapid enforcement of paternity. HP-I mutant males were ineffective in enforcing paternity when a second male was given access to the female within 1 hour. NPYLR1 mutant females produced mixed paternity offspring at high frequency. Synthetic HP-I injected into wild-type virgins reduced successful matings, but had no effect on NPYLR1 mutant females. Asian tiger mosquito (Ae. albopictus) HP-I potently activated Ae. aegypti NPYLR1. Invasive Ae. albopictus males are known to copulate with and sterilize Ae. aegypti females, and cross-species transfer of HP-I may contribute to this phenomenon. This neuropeptide system promotes rapid paternity enforcement within Ae. aegypti, but may promote local extinction in areas where they compete with Ae. albopictus.\n\nOne Sentence SummaryAedes-specific peptide rapidly enforces paternity\n\nTextAe. aegypti females typically mate only once with one male in their lifetime, a behavior known as \"monandry\" (1). This single mating event provisions the female with sufficient sperm to fertilize the >500 eggs she will produce during her [~]4-6 week lifespan in the laboratory (2). Successful mating is capable of inducing lifetime refractoriness to subsequent insemination by other males, enforcing the paternity of the first male (3-5). In other species, males use diverse strategies to assure the paternity of their offspring, for instance physical barriers such as mating plugs found in mice (6) and Anopheline mosquitoes (7), and anti-aphrodisiac pheromones used by Drosophila melanogaster males to tag female flies as non-virgin (8). Another widely used strategy in insects is the transfer of biologically active male seminal proteins, produced by the male accessory gland and secreted into the ejaculatory duct along with sperm during insemination, to affect the sexual receptivity of the female (3, 9-13). Perhaps the best-characterized male seminal fluid protein in insects is the Drosophila fly sex peptide (11), which acts on the sex peptide receptor in the female to suppress receptivity and trigger egg production (12). Drosophila sex peptide receptor mutant females will readily remate with multiple males, and wild-type females that mate with sex peptide mutant males remain sexually receptive.

neuroscience↗