Background: mTORC1 plays an important role in the regulation of TOP mRNA translation. Results: LARP1 is a target of mTORC1 that associates with TOP mRNAs via their 5ЈTOP motif to repress their translation. Conclusion: LARP1 represses TOP mRNA translation downstream of mTORC1. Significance: We elucidate an important novel signaling pathway downstream of mTORC1 that controls the production of ribosomes and translation factors in eukaryotic cells.
The monocytic leukemia zinc finger protein MOZ and the related factor MORF form tetrameric complexes with ING5 (inhibitor of growth 5), EAF6 (Esa1-associated factor 6 ortholog), and the bromodomain-PHD finger protein BRPF1, -2, or -3. To gain new insights into the structure, function, and regulation of these complexes, we reconstituted them and performed various molecular analyses. We found that BRPF proteins bridge the association of MOZ and MORF with ING5 and EAF6. An N-terminal region of BRPF1 interacts with the acetyltransferases; the enhancer of polycomb (EPc) homology domain in the middle part binds to ING5 and EAF6. The association of BRPF1 with EAF6 is weak, but ING5 increases the affinity. These three proteins form a trimeric core that is conserved from Drosophila melanogaster to humans, although authentic orthologs of The gene of MOZ (monocytic leukemia zinc finger protein, also referred to as MYST3 and KAT6A), located on chromosome 8p11, was first identified as a fusion partner in chromosome translocation t(8;16)(p11;p13) (2, 52). This recurrent translocation is associated with a monocytic subtype of acute myeloid leukemia and results in the fusion of the MOZ Nterminal domain to the C-terminal part of the transcription coactivator CBP. Two other leukemia-associated chromosomal rearrangements lead to the expression of proteins fusing MOZ fragments to the CBP paralog p300 and the p300/CBP-interacting nuclear receptor coactivator TIF2 (transcription intermediary factor 2, also known as steroid receptor coactivator 2 [SRC-2] and nuclear receptor coactivator 2 [NCOA2]) (6,8,29,34). One of the resulting fusion proteins, MOZ-TIF2, is known to promote self-renewal of leukemic stem cells (17,25), suggesting that the chromosome abnormalities play a causal role in leukemogenesis. In addition, it was recently reported that MOZ is fused to NCOA3 (22), a TIF2 paralog synonymous with SRC-3 and AIB1 (amplified in breast cancer 1). MOZ is highly homologous to MORF (MOZ-related factors, also named Querkopf, MYST4, and KAT6B) (11,64). The MORF gene is rearranged in leukemia patients with t(10; 16)(q22;p13) (46) and in leiomyoma cases with t(10;17)(p11; q21) (40). The CBP gene is the fusion partner in the former translocation, while the GCN5 gene is a potential candidate in the latter translocation. All of these findings suggest that deregulated acetylation has an important role in oncogenesis. In addition, recent studies indicate that MOZ and MORF play key roles in hematopoiesis, skeletogenesis, neurogenesis, and other developmental processes (16,26,38,39,62,64). Therefore, MOZ and MORF are intimately linked to both normal development and cancer development (63,69).At the molecular level, available data suggest that this pair of paralogs functions as transcriptional coactivators with intrinsic histone acetyltransferase (HAT) activity (3,11,12,27,28,48). Both possess the MYST domain, a catalytic core conserved among members of the MYST family of acetyltransferases (2, 52). Within this family, there are five members in hu...
Advances in sequencing and high-throughput techniques have provided an unprecedented opportunity to interrogate human diseases on a genome-wide scale. The list of disease-causing mutations is expanding rapidly, and mutations affecting mRNA translation are no exception. Translation (protein synthesis) is one of the most complex processes in the cell. The orchestrated action of ribosomes, tRNAs and numerous translation factors decodes the information contained in mRNA into a polypeptide chain. The intricate nature of this process renders it susceptible to deregulation at multiple levels. In this Review, we summarize current evidence of translation deregulation in human diseases other than cancer. We discuss translation-related diseases on the basis of the molecular aberration that underpins their pathogenesis (including tRNA dysfunction, ribosomopathies, deregulation of the integrated stress response and deregulation of the mTOR pathway) and describe how deregulation of translation generates the phenotypic variability observed in these disorders.
Translational control of gene expression plays a key role during the early phases of embryonic development. Here we describe a transcriptional regulator of mouse embryonic stem cells (mESCs), Yin-yang 2 (YY2), that is controlled by the translation inhibitors, Eukaryotic initiation factor 4E-binding proteins (4E-BPs). YY2 plays a critical role in regulating mESC functions through control of key pluripotency factors, including Octamer-binding protein 4 (Oct4) and Estrogen-related receptor-β (Esrrb). Importantly, overexpression of YY2 directs the differentiation of mESCs into cardiovascular lineages. We show that the splicing regulator Polypyrimidine tractbinding protein 1 (PTBP1) promotes the retention of an intron in the 5′-UTR of Yy2 mRNA that confers sensitivity to 4E-BP-mediated translational suppression. Thus, we conclude that YY2 is a major regulator of mESC self-renewal and lineage commitment and document a multilayer regulatory mechanism that controls its expression.mRNA translation | 4E-BPs | PTBP | embryonic stem cell | YY2
Simultaneous measurements of mRNA and protein abundance and turnover in mammalian cells, have revealed that a significant portion of the cellular proteome is controlled by mRNA translation. Recent studies have demonstrated that both embryonic and somatic stem cells are dependent on low translation rates to maintain an undifferentiated state. Conversely, differentiation requires increased protein synthesis and failure to do so prevents differentiation. Notably, the low translation in stem cell populations is independent of the cell cycle, indicating that stem cells use unique strategies to decouple these fundamental cellular processes. In this chapter, we discuss different mechanisms used by stem cells to control translation, as well as the developmental consequences of translational deregulation.
Activation of microglia in the spinal cord following peripheral nerve injury is critical for the development of long-lasting pain hypersensitivity. However, it remains unclear whether distinct microglia subpopulations or states contribute to different stages of pain development and maintenance. Using single-cell RNA-sequencing, we show that peripheral nerve injury induces the generation of a male-specific inflammatory microglia subtype, and demonstrate increased proliferation of microglia in male as compared to female mice. We also show time- and sex-specific transcriptional changes in different microglial subpopulations following peripheral nerve injury. Apolipoprotein E (Apoe) is the top upregulated gene in spinal cord microglia at chronic time points after peripheral nerve injury in mice. Furthermore, polymorphisms in the APOE gene in humans are associated with chronic pain. Single-cell RNA sequencing analysis of human spinal cord microglia reveals a subpopulation with a disease-related transcriptional signature. Our data provide a detailed analysis of transcriptional states of mouse and human spinal cord microglia, and identify a link between ApoE and chronic pain in humans.
Translational control plays a pivotal role in the regulation of the pluripotency network in embryonic stem cells, but its effect on reprogramming somatic cells to pluripotency has not been explored. Here, we show that eukaryotic translation initiation factor 4E (eIF4E) binding proteins (4E-BPs), which are translational repressors, have a multifaceted effect on the reprogramming of mouse embryonic fibroblasts (MEFs) into induced pluripotent stem cells (iPSCs). Loss of 4E-BP expression attenuates the induction of iPSCs at least in part through increased translation of p21, a known inhibitor of somatic cell reprogramming. However, MEFs lacking both p53 and 4E-BPs show greatly enhanced reprogramming resulting from a combination of reduced p21 transcription and enhanced translation of endogenous mRNAs such as Sox2 and Myc and can be reprogrammed through the expression of only exogenous Oct4. Thus, 4E-BPs exert both positive and negative effects on reprogramming, highlighting the key role that translational control plays in regulating this process.
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