Regulation Of Elongation Research Articles

The transcription factor GhMYB4 represses lipid transfer and sucrose transporter genes and inhibits fiber cell elongation in cotton.

Cotton (Gossypium hirsutum) fiber is a highly elongated single cell with a thickened cell wall. MYB transcription factors are important regulators of plant cell elongation; however, the molecular mechanism involved in regulating fiber elongation remains to be explored. Here, we present evidence that the R2R3-MYB transcription factor GhMYB4 negatively regulates cotton fiber cell elongation by suppressing the expression of two crucial genes previously reported to affect fiber development: lipid transfer protein 4 (GhLTP4) and sucrose transporter 12 (GhSWEET12). GhMYB4 is preferentially expressed in elongating fiber cells. Knockdown of GhMYB4 in cotton results in longer fiber cells, whereas overexpression of GhMYB4 in Arabidopsis leads to reduced plant height and root length. Transcriptomic and lipidomic analyses revealed that GhMYB4 is involved in coordinating three interconnected biological processes, namely lipid content regulation, auxin signaling, and sugar metabolism. Additionally, we showed that GhMYB4 inhibits the expression of GhLTP4 and GhSWEET12 by binding to the MYB cis-element (TTTAGTG) in their respective promoters. Interestingly, bHLH transcription factor 105 (GhbHLH105) and MYB transcription factor 212 (GhMYB212) counteract the inhibitory effects of GhMYB4 on the expression of GhLTP4 and GhSWEET12, respectively. These findings provide insights into the complex molecular mechanisms regulating plant cell elongation.

A natural variation of TaERF-A1 encoding an AP2/ERF transcription factor confers semidwarf plant architecture and increased lodging resistance in wheat

The introduction of Reduced height (Rht) genes into wheat varieties results in semidwarf plant architecture with largely improved lodging resistance and harvest indices. Therefore, the exploration of new Rht gene resources to breed semidwarf wheat cultivars has been a major strategy for guaranteeing high and stable grain yields of wheat since the 1960s. In this study, we report the map-based cloning of TaERF-A1, which encodes an AP2/ERF transcription factor and acts as a positive regulator of wheat stem elongation, as a new gene for regulating plant height and spike length. The natural variant TaERF-A1JD6, characterized by a substitution from Phe (derived from Nongda3338) to Ser (derived from Jingdong6) at position 178, significantly weakened the stability of the TaERF-A1 protein. As a result, this substitution led to partly attenuated transcriptional activation of TaERF-A1-targeted downstream genes, including TaPIF4, resulting in the restriction of stem and spike elongation. Importantly, introgression of the semidwarfing-related allele TaERF-A1JD6 in wheat materials significantly enhanced lodging resistance, especially in dense cropping systems. Therefore, our study reveals TaERF-A1JD6 as a new Rht gene resource for breeding semidwarf wheat varieties with increased yield stability.

Cellular and molecular mechanisms that shape the development and evolution of tail vertebral proportion in mice and jerboas.

Despite the functional importance of the vertebral skeleton, little is known about how individual vertebrae elongate or achieve disproportionate lengths as in the giraffe neck. Rodent tails are an abundantly diverse and more tractable system to understand mechanisms of vertebral growth and proportion. In many rodents, disproportionately long mid-tail vertebrae form a 'crescendo-decrescendo' of lengths in the tail series. In bipedal jerboas, these vertebrae grow exceptionally long such that the adult tail is 1.5x the length of a mouse tail, relative to body length, with four fewer vertebrae. How do vertebrae with the same regional identity elongate differently from their neighbors to establish and diversify adult proportion? Here, we find that vertebral lengths are largely determined by differences in growth cartilage height and the number of cells progressing through endochondral ossification. Hypertrophic chondrocyte size, a major contributor to differential elongation in mammal limb bones, differs only in the longest jerboa mid-tail vertebrae where they are exceptionally large. To uncover candidate molecular mechanisms of disproportionate vertebral growth, we performed intersectional RNA-Seq of mouse and jerboa tail vertebrae with similar and disproportionate elongation rates. Many regulators of posterior axial identity and endochondral elongation are disproportionately differentially expressed in jerboa vertebrae. Among these, the inhibitory natriuretic peptide receptor C (NPR3) appears in multiple studies of rodent and human skeletal proportion suggesting it refines local growth rates broadly in the skeleton and broadly in mammals. Consistent with this hypothesis, NPR3 loss of function mice have abnormal tail and limb proportions. Therefore, in addition to genetic components of the complex process of vertebral evolution, these studies reveal fundamental mechanisms of skeletal growth and proportion.

Synaptotagmin 4 Supports Spontaneous Axon Sprouting after Spinal Cord Injury.

Injuries to the central nervous system (CNS) can cause severe neurological deficits. Axonal regrowth is a fundamental process for the reconstruction of compensatory neuronal networks after injury; however, it is extremely limited in the adult mammalian CNS. In this study, we conducted a loss-of-function genetic screen in cortical neurons, combined with a Web resource-based phenotypic screen, and identified synaptotagmin 4 (Syt4) as a novel regulator of axon elongation. Silencing Syt4 in primary cultured cortical neurons inhibits neurite elongation, with changes in gene expression involved in signaling pathways related to neuronal development. In a spinal cord injury model, inhibition of Syt4 expression in cortical neurons prevented axonal sprouting of the corticospinal tract, as well as neurological recovery after injury. These results provide a novel therapeutic approach to CNS injury by modulating Syt4 function.

MmpL3, Wag31, and PlrA are involved in coordinating polar growth with peptidoglycan metabolism and nutrient availability.

This study is performed in Mycobacterium smegmatis, which is used as a model to understand the basic physiology of pathogenic mycobacteria such as Mycobacterium tuberculosis. In this work, we examine the function and regulation of three proteins involved in regulating cell wall elongation in mycobacterial cells, which occurs at the cell tips or poles. We find that Wag31, a regulator of polar elongation, works partly through the regulation of MmpL3, a transporter of cell wall constituents and an important drug target. Our work suggests that, beyond its transport function, MmpL3 has another function in controlling cell wall synthesis broadly in response to stress.

Chromatin protein complexes involved in gene repression in lamina-associated domains

Lamina-associated domains (LADs) are large chromatin regions that are associated with the nuclear lamina (NL) and form a repressive environment for transcription. The molecular players that mediate gene repression in LADs are currently unknown. Here, we performed FACS-based whole-genome genetic screens in human cells using LAD-integrated fluorescent reporters to identify such regulators. Surprisingly, the screen identified very few NL proteins, but revealed roles for dozens of known chromatin regulators. Among these are the negative elongation factor (NELF) complex and interacting factors involved in RNA polymerase pausing, suggesting that regulation of transcription elongation is a mechanism to repress transcription in LADs. Furthermore, the chromatin remodeler complex BAF and the activation complex Mediator can work both as activators and repressors in LADs, depending on the local context and possibly by rewiring heterochromatin. Our data indicate that the fundamental regulators of transcription and chromatin remodeling, rather than interaction with NL proteins, play a major role in transcription regulation within LADs.

Regulatory networks of coresident subgenomes during rapid fiber cell elongation in upland cotton

Cotton, an intriguing plant species shaped by polyploidization, evolution, and domestication, holds particular interest due to the complex mechanisms governing fiber traits across its two subgenomes. However, the regulatory elements or transcriptional networks between subgenomes during fiber elongation remain to be fully clarified. Here, we analyzed 1462 cotton fiber samples to reconstruct the gene-expression regulatory networks that influence fiber cell elongation. Inter-subgenome expression quantitative trait loci (eQTLs) largely dictate gene transcription, with a notable tendency for the D subgenome to regulate A-subgenome eGenes. This regulation reveals synchronized homoeologous gene expression driven by co-localized eQTLs and divergent patterns that diminish genetic correlations, thus leading to preferential expression in the A and D subgenomes. Hotspot456 emerged as a key regulator of fiber initiation and elongation, and artificial selection of trans-eQTLs in hotspot456 that positively regulate KCS1 has facilitated cell elongation. Experiments designed to clarify the roles of trans-eQTLs in improved fiber breeding confirmed the inhibition of GhTOL9 by a specific trans-eQTL via GhWRKY28, which negatively affects fiber elongation. We propose a model in which the GhWRKY28–GhTOL9 module regulates this process through the ESCRT (endosomal sorting complex required for transport) pathway. This research significantly advances our understanding of cotton’s evolutionary and domestication processes and the intricate regulatory mechanisms that underlie significant plant traits.

New insight into process pH regulation on caproate production from waste activated sludge acidogenic fermentation liquid by cathodic electro-fermentation

Cathodic electro-fermentation (CEF) has been proven to enhance the production of caproate from biowaste by improving chain elongation metabolism. However, the impact of process pH control in catholyte to avoid pH changes caused by redox reactions under polarized cathode on chain elongation has been rarely reported. Here the caproate production performances from waste activated sludge acidogenic fermentation liquid were evaluated and compared between different process pHs of 5.5, 6.0, and 6.5 with control group at 0.9 V. Results demonstrated the maximum caproate concentration was reached 4.1 g/L at pH 6.0, which was significantly higher than the 2.7 g/L of the control group, indicating the benefits of pH control on chain elongation metabolism in CEF. Mechanisms analysis revealed that the enhancement of pH regulation was attributed to the enrichment of organic degraders (Pseudomonas) in catholyte and the increased metabolic activity (like acetyl-CoA carboxylase) of chain elongator (Clostridium_sensus_stricto_12) on biofilm. These results were evidenced by the improved release and conversion performance of substrates (especially the amino acids) in catholyte and the enhanced biofilm activity. Hence, this study contributes novel insights to the pH regulation of chain elongation for enhancing caproate production from biowaste by electro-fermentation.

Targeting Super-Enhancer-Driven Transcriptional Dependencies Suppresses Aberrant Hedgehog Pathway Activation and Overcomes Smoothened Inhibitor Resistance.

Aberrant activation of the Hedgehog (Hh) signaling pathway plays important roles in oncogenesis and therapeutic resistance in several types of cancer. The clinical application of FDA-approved Hh-targeted smoothened inhibitors (SMOi) is hindered by the emergence of primary or acquired drug resistance. Epigenetic and transcriptional-targeted therapies represent a promising direction for developing improved anti-Hh therapies. In this study, we integrated epigenetic/transcriptional-targeted small-molecule library screening with CRISPR/Cas9 knockout library screening and identified CDK9 and CDK12, two transcription elongation regulators, as therapeutic targets for antagonizing aberrant Hh activation and overcoming SMOi resistance. Inhibition of CDK9 or CDK12 potently suppressed Hh signaling and tumor growth in various SMOi responsive or resistant Hh-driven tumor models. Systemic epigenomic profiling elucidated the Hh-driven super-enhancer (SE) landscape and identified IRS1, encoding a critical component and cytoplasmic adaptor protein of the insulin-like growth factor (IGF) pathway, as an oncogenic Hh-driven SE target gene and effective therapeutic target in Hh-driven tumor models. Collectively, this study identifies SE-driven transcriptional dependencies that represent promising therapeutic vulnerabilities for suppressing the Hh pathway and overcoming SMOi resistance. As CDK9 and IRS inhibitors have already entered human clinical trials for cancer treatment, these findings provide comprehensive preclinical support for developing trials for Hh-driven cancers. Significance: Dissecting transcriptional dependencies driven by super-enhancers uncovers therapeutic targets in Hedgehog-driven cancers and identifies strategies for overcoming resistance to smoothened inhibitors.

Temporal and spatial frameworks supporting plant responses to vegetation proximity.

After the perception of vegetation proximity by phytochrome photoreceptors, shade-avoider plants initiate a set of responses known as the shade avoidance syndrome (SAS). Shade perception by the phytochrome B (phyB) photoreceptor unleashes the PHYTOCHROME INTERACTING FACTORs and initiates SAS responses. In Arabidopsis (Arabidopsis thaliana) seedlings, shade perception involves rapid and massive changes in gene expression, increases auxin production, and promotes hypocotyl elongation. Other components, such as phyA and ELONGATED HYPOCOTYL 5, also participate in the shade regulation of the hypocotyl elongation response by repressing it. However, why and how so many regulators with either positive or negative activities modulate the same response remains unclear. Our physiological, genetic, cellular, and transcriptomic analyses showed that (i) these components are organized into 2 main branches or modules and (ii) the connection between them is dynamic and changes with the time of shade exposure. We propose a model for the regulation of shade-induced hypocotyl elongation in which the temporal and spatial functional importance of the various SAS regulators analyzed here helps to explain the coexistence of differentiated regulatory branches with overlapping activities.

The chloroplast pentatricopeptide repeat protein RCN22 regulates tiller number in rice by affecting sugar levels via the TB1–RCN22–RbcL module

As an important yield component, rice tiller number controls panicle number and determines grain yield. Regulation of rice tiller number by chloroplast pentatricopeptide repeat (PPR) proteins has not been reported previously. Here, we report the rice reduced culm number22 (rcn22) mutant, which produces few tillers owing to suppressed tiller bud elongation. Map-based cloning revealed that RCN22 encodes a chloroplast-localized P-type PPR protein. We found that RCN22 specifically binds to the 5′ UTR of RbcL mRNA (encoding the large subunit of Rubisco) and enhances its stability. The reduced abundance of RbcL mRNA in rcn22 leads to a lower photosynthetic rate and decreased sugar levels. Consequently, transcript levels of DWARF3 (D3) and TEOSINTE BRANCHED1 (TB1) (which encode negative regulators of tiller bud elongation) are increased, whereas protein levels of the positive regulator DWARF53 (D53) are decreased. Furthermore, high concentrations of sucrose can rescue the tiller bud growth defect of the rcn22 mutant. On the other hand, TB1 directly binds to the RCN22 promoter and downregulates its expression. The tb1/rcn22 double mutant shows a tillering phenotype similar to that of rcn22. Our results suggest that the TB1–RCN22–RbcL module plays a vital role in rice tiller bud elongation by affecting sugar levels.

Puff, the polytene chromosome: Visualizing transcription elongation control

In this issue, Versluis etal.1 use a highly sensitive live-cell imaging system to examine transcription dynamics and functions of various key transcription elongation regulators at the Hsp70 loci.

GhMAX2 Contributes to Auxin-Mediated Fiber Elongation in Cotton (Gossypium hirsutum).

Strigolactones (SLs) represent a new group of phytohormones that play a pivotal role in the regulation of plant shoot branching and the development of adventitious roots. In cotton (Gossypium hirsutum, Gh), SLs play a crucial role in the regulation of fiber cell elongation and secondary cell wall thickness. However, the underlying molecular mechanisms of SL signaling involved in fiber cell development are largely unknown. In this study, we report two SL-signaling genes, GhMAX2-3 and GhMAX2-6, which positively regulate cotton fiber elongation. Further protein-protein interaction and degradation assays showed that the repressor of the auxin cascade GhIAA17 serves as a substrate for the F-box E3 ligase GhMAX2. The in vivo ubiquitination assay suggested that GhMAX2-3 and GhMAX2-6 ubiquitinate GhIAA17 and coordinately degrade GhIAA17 with GhTIR1. The findings of this investigation offer valuable insights into the roles of GhMAX2-mediated SL signaling in cotton and establish a solid foundation for future endeavors aimed at optimizing cotton plant cultivation.

Integrating GWAS, RNA-Seq and functional analysis revealed that BnaA02.SE mediates silique elongation by affecting cell proliferation and expansion in Brassica napus.

Rapeseed (Brassica napus) silique is the major carbohydrate source for seed development, and the final silique length has attracted great attention from breeders. However, no studies had focused on the dynamic character of silique elongation length (SEL). Here, the dynamic SEL investigation in a natural population including 588 lines over two years indicate that dynamic SEL during 0-20 days after flowering was the most essential stage associated with seed number per silique (SPS) and thousand seed weight (TSW). Then, nine loci were identified to be associated with SEL based on GWAS analysis, among which five SNPs (over 50%) distributed on the A02 chromosome within 6.08 to 6.48 Mb. Subsequently, we screened 5078 differentially expressed genes between two extreme materials. An unknown protein, BnaA02.SE, was identified combining with GWAS and RNA-Seq analysis. Subcellular localization and expression profiles analysis demonstrated that BnaA02.SE is a chloroplast- and nucleus-localized protein mainly expressed in pericarps and leaves. Furthermore, transgenic verification and dynamic cytological observation reveal that overexpressed BnaA02.SE can promote silique elongation by regulating JA and IAA contents, affecting cell proliferation and expansion, respectively, and finally enhance seed yield by influencing SPS and TSW. Haplotype analysis reveal that the homologs of BnaA02.SE may also be involved in silique elongation regulation. Our findings provided comprehensive insights into a newly SEL trait, and cloned the first gene (BnaA02.SE) controlling silique elongation in B. napus. The identified BnaA02.SE and its homologs can offer a valuable target for improving B. napus yield.

Abstract B006: Data-driven discoveries of molecular mechanism and therapeutic vulnerabilities of CDK12 mutant tumors

Abstract Somatic structural variations (SVs) are common in cancer. Although a small fraction of SVs in breast and ovarian cancers can be attributed to homologous recombination deficiency, the underlying molecular mechanisms for the vast majority of somatic SVs remain unclear. Here, we focus on the roles of transcription and DNA replication collisions in genomic instability in cancer. Such collisions are unavoidable in cells since both transcription and replication use the same DNA as template. We hypothesized that transcription replication collisions (TRCs), if not properly repaired, would lead to collapsed replication forks and result in SVs. To this end, we studied somatic SVs in 6193 high-coverage whole-genome sequenced primary and metastatic tumors from three independent pan-cancer cohorts. A total of 13 conserved SV signatures, representing independent molecular mechanisms, were deconvoluted from these cohorts using non-negative matrix factorization approach. We detected replicated-strand bias, the expected footprint of transcription-replication collision, in large tandem duplications (TDs) across multiple cohorts. This bias was only observed in expressed genes, consistent with TRCs depending on transcription activity. Large TDs were abundant in female-specific (breast, ovarian and uterus), upper gastric-intestinal tract, and prostate cancers. They were associated with CDK12 mutations and worse patient survival. CDK12 is a cyclin-dependent kinase, a key regulator of transcription elongation and termination. Deleting or suppressing CDK12 using CRISPR-Cas9 in prostate cell lines increased RNA:DNA hybrids (R-loops), promoted TRCs, and ultimately led to large TDs. Finally, we found that cells lacking CDK12 were sensitive to WEE1, CHK1 and ATR inhibitors. In summary, our data suggest that large TDs in cancer form due to impaired TRC repair and can be used as a biomarker for prognosis and treatment. Citation Format: Lixing Yang. Data-driven discoveries of molecular mechanism and therapeutic vulnerabilities of CDK12 mutant tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B006.

Genetic and Molecular Regulation of Cotton Fiber Initiation and Elongation

Cotton fiber, a crucial and sustainable resource for global textile production, undergoes a complex five-stage developmental process, encompassing initiation, elongation, transition, secondary cell wall biosynthesis, and maturation. These elongated single-cell fibers originate from the outer ovule epidermis. The development of cotton fibers involves intricate changes in gene expression and physiological processes, resulting in a nearly pure cellulose product that is vital for the global cotton industry. Decoding the genes associated with fiber development enhances our understanding of cotton fiber mechanisms and facilitates the cultivation of varieties with enhanced quality. In recent decades, advanced omics approaches, including genomics, transcriptomics, and proteomics, have played a pivotal role in identifying the genes and gene products linked to cotton fiber development, including the MYB transcription factor family, which coordinates cotton fiber development. Molecular studies have revealed the transcription factors, like MYB, WRKY, Homeodomain Leucine Zipper (HD-ZIP), and basic helix–loop–helix (bHLH), influencing fiber initiation and elongation. The intricate interplay of phytohormones, like auxin, gibberellic acid (GA), brassinosteroids (BRs), jasmonic acid (JA), ethylene, abscisic acid (ABA), and cytokinin, is explored, providing a comprehensive perspective on the shaping of cotton fibers. Numerous candidate genes and cellular processes affecting various aspects of fiber development hold promise for genetic engineering or marker-assisted breeding to improve fiber quality. This review presents a comprehensive overview of key achievements in cotton molecular biology, with a specific emphasis on recent advancements in understanding the transcription factors and phytohormones involved in cotton fiber initiation and elongation.

The interplay of homology-directed repair pathways in the repair of zebularine-induced DNA-protein crosslinks in Arabidopsis.

DNA-protein crosslinks (DPCs) are highly toxic DNA lesions represented by proteins covalently bound to the DNA. Persisting DPCs interfere with fundamental genetic processes such as DNA replication and transcription. Cytidine analog zebularine (ZEB) has been shown to crosslink DNA METHYLTRANSFERASE1 (MET1). Recently, we uncovered a critical role of the SMC5/6-mediated SUMOylation in the repair of DPCs. In an ongoing genetic screen, we identified two additional candidates, HYPERSENSITIVE TO ZEBULARINE 2 and 3, that were mapped to REGULATOR OF TELOMERE ELONGATION 1 (RTEL1) and polymerase TEBICHI (TEB), respectively. By monitoring the growth of hze2 and hze3 plants in response to zebularine, we show the importance of homologous recombination (HR) factor RTEL1 and microhomology-mediated end-joining (MMEJ) polymerase TEB in the repair of MET1-DPCs. Moreover, genetic interaction and sensitivity assays showed the interdependency of SMC5/6 complex, HR, and MMEJ in the homology-directed repair of MET1-DPCs in Arabidopsis. Altogether, we provide evidence that MET1-DPC repair in plants is more complex than originally expected.

Down-regulation of RTEL1 Improves M1/M2 Macrophage Polarization by Promoting SFRP2 in Fibroblasts-derived Exosomes to Alleviate COPD.

Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory disease worldwide. Macrophage polarization plays a substantial role in the pathogenesis of COPD. This study is aimed to explore the regulatory mechanism of regulator of telomere elongation 1 (RTEL1) in COPD. COPD model mouse was conducted by cigarette smoke (CS). The pathological features of lung in mice were observed by histological staining. After extracting exosomes, macrophages were co-cultured with fibroblasts-derived exosomes. Then, the effects of RTEL1 and exosomal secreted frizzled-related protein 2 (SFRP2) on macrophage proliferation, inflammation, apoptosis, and M1, M2 macrophage polarization (iNOS and CD206) were evaluated by cell counting kit-8, EdU assay, enzyme-linked immuno sorbent assay, and western blotting, respectively. CS-induced COPD model mouse was successfully constructed. Through in vitro experiments, knockdown of RTEL1 inhibited macrophage proliferation, inflammation (MMP9, IL-1β and TNF-α), and promoted apoptosis (Bax, cleaved-caspase3, Bcl-2) in CS extract-induced lung fibroblasts. Meanwhile, RTEL1 knockdown promoted M1 and suppressed M2 macrophage polarization in COPD. Additionally, silencing SFRP2 in fibroblasts-derived exosomes reversed the effects of RTEL1 knockdown on proliferation, inflammation, apoptosis, and M1, M2 macrophage polarization. Collectively, down-regulation of RTEL1 improved M1/M2 macrophage polarization by promoting SFRP2 in fibroblasts-derived exosomes to alleviate CS-induced COPD.

Regulation of root growth and elongation in wheat.

Currently, the control of rhizosphere selection on farms has been applied to achieve enhancements in phenotype, extending from improvements in single root characteristics to the dynamic nature of entire crop systems. Several specific signals, regulatory elements, and mechanisms that regulate the initiation, morphogenesis, and growth of new lateral or adventitious root species have been identified, but much more work remains. Today, phenotyping technology drives the development of root traits. Available models for simulation can support all phenotyping decisions (root trait improvement). The detection and use of markers for quantitative trait loci (QTLs) are effective for enhancing selection efficiency and increasing reproductive genetic gains. Furthermore, QTLs may help wheat breeders select the appropriate roots for efficient nutrient acquisition. Single-nucleotide polymorphisms (SNPs) or alignment of sequences can only be helpful when they are associated with phenotypic variation for root development and elongation. Here, we focus on major root development processes and detail important new insights recently generated regarding the wheat genome. The first part of this review paper discusses the root morphology, apical meristem, transcriptional control, auxin distribution, phenotyping of the root system, and simulation models. In the second part, the molecular genetics of the wheat root system, SNPs, TFs, and QTLs related to root development as well as genome editing (GE) techniques for the improvement of root traits in wheat are discussed. Finally, we address the effect of omics strategies on root biomass production and summarize existing knowledge of the main molecular mechanisms involved in wheat root development and elongation.

The autism susceptibility kinase, TAOK2, phosphorylates eEF2 and modulates translation.

Genes implicated in translation control have been associated with autism spectrum disorders (ASDs). However, some important genetic causes of autism, including the 16p11.2 microdeletion, bear no obvious connection to translation. Here, we use proteomics, genetics, and translation assays in cultured cells and mouse brain to reveal altered translation mediated by loss of the kinase TAOK2 in 16p11.2 deletion models. We show that TAOK2 associates with the translational machinery and functions as a translational brake by phosphorylating eukaryotic elongation factor 2 (eEF2). Previously, all signal-mediated regulation of translation elongation via eEF2 phosphorylation was believed to be mediated by a single kinase, eEF2K. However, we show that TAOK2 can directly phosphorylate eEF2 on the same regulatory site, but functions independently of eEF2K signaling. Collectively, our results reveal an eEF2K-independent signaling pathway for control of translation elongation and suggest altered translation as a molecular component in the etiology of some forms of ASD.