Youngseob Jung

Yale University

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Kyong‐Tai Kim

Pohang University of Science and Technology

Hye Guk Ryu

Chungbuk National University

Kyung‐Ha Lee

Pusan National University

Do‐Yeon Kim

Ewha Womans University

Jiyoung Seo

Pohang University of Science and Technology

Sung Wook Kim

Pohang University of Science and Technology

Hwa‐Rim Lee

Pohang University of Science and Technology

Sung Key Jang

Pohang University of Science and Technology

Janghoo Lim

Yale University

Hyojin Kim

Baekseok University

Cooperative Institutions

Pohang University of Science and Technology

Yale University

Yonsei University

Korea Research Institute of Bioscience and Biotechnology

Korea University

Government of the Republic of Korea

Korea Advanced Institute of Science and Technology

Kyung Hee University

Seoul National University

Kyungpook National University

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Upf1 regulates neurite outgrowth and branching by transcriptional and post-transcriptional modulation of Arc

Journal of Cell Science (2018)

Hye Guk Ryu Jiyoung Seo Youngseob Jung Sung Wook Kim Eunah Kim

ABSTRACT A large number of neuronal proteins must show correct spatiotemporal localization in order to carry out their critical functions. The mRNA transcript for the somatodendritic protein activity-regulated cytoskeleton-associated protein (Arc; also known as Arg3.1) contains two conserved introns in the 3′ untranslated region (UTR), and was proposed to be a natural target for nonsense-mediated mRNA decay (NMD). However, a well-known NMD component Upf1 has differential roles in transcriptional and translational regulation of Arc gene expression. Specifically, Upf1 suppresses Arc transcription by enhancing destabilization of mRNAs encoding various transcription factors, including Mef2a. Upf1 also binds to the Arc 3′UTR, resulting in suppression of translation. Surprisingly, the Arc transcript escapes from Upf1-mediated NMD by binding to Ago2 (also known as miRISC), which blocks NMD and further suppresses Arc mRNA translation. Upf1 knockdown triggered sustained Arc expression, which contributes to Cofilin (also known as Cfl1) hyperphosphorylation and abnormal neuronal outgrowth and branching. Collectively, these data reveal that multiple levels of Upf1-mediated inhibition of Arc gene expression may allow neurons to more effectively respond to changes in neuronal activity.

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Neurite

10.1242/jcs.224055

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Citations (5)

BDNF-induced local translation of GluA1 is regulated by HNRNP A2/B1

Science Advances (2020)

Youngseob Jung Jiyoung Seo Hye Guk Ryu Do‐Yeon Kim Kyung‐Ha Lee

The AMPA receptor subunit GluA1 is essential for induction of synaptic plasticity. While various regulatory mechanisms of AMPA receptor expression have been identified, the underlying mechanisms of GluA1 protein synthesis are not fully understood. In neurons, axonal and dendritic mRNAs have been reported to be translated in a cap-independent manner. However, molecular mechanisms of cap-independent translation of synaptic mRNAs remain largely unknown. Here, we show that GluA1 mRNA contains an internal ribosome entry site (IRES) in the 5'UTR. We also demonstrate that heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 interacts with GluA1 mRNA and mediates internal initiation of GluA1 Brain-derived neurotrophic factor (BDNF) stimulation increases IRES-mediated GluA1 translation via up-regulation of HNRNP A2/B1. Moreover, BDNF-induced GluA1 expression and dendritic spine density were significantly decreased in neurons lacking hnRNP A2/B1. Together, our data demonstrate that IRES-mediated translation of GluA1 mRNA is a previously unidentified feature of local expression of the AMPA receptor.

Heterogeneous nuclear ribonucleoprotein

10.1126/sciadv.abd2163

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The RNA-binding protein hnRNP Q represses translation of the clock gene Bmal1 in murine cells

Journal of Biological Chemistry (2019)

Youngseob Jung Hye Guk Ryu Sung Wook Kim Kyung‐Ha Lee Sohyun Gu

Translational regulation

10.1074/jbc.ra118.006947

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Citations (3)

Adaptive Search Engine Using Ranking Support Vector Machine

Wooram Heo Haeryun Yang Youngseob Jung Ho-Jin Choi

Ranking SVM

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Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43–related neurodegeneration

Journal of Clinical Investigation (2023)

Leon Tejwani Youngseob Jung Hiroshi Kokubu Sowmithra Sowmithra Luhan Ni

Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP, encoding TDP-43, account for less than 1% of all ALS cases, TDP-43-positive aggregates are present in nearly all ALS patients, including patients with sporadic ALS (sALS) or carrying other familial ALS (fALS)-causing mutations. Interestingly, TDP-43 inclusions are also present in subsets of patients with frontotemporal dementia, Alzheimer's disease, and Parkinson's disease; therefore, methods of activating intracellular protein quality control machinery capable of clearing toxic cytoplasmic TDP-43 species may alleviate disease-related phenotypes. Here, we identify a novel function of Nemo-like kinase (Nlk) as a negative regulator of lysosome biogenesis. Genetic or pharmacological reduction of Nlk increased lysosome formation and improved clearance of aggregated TDP-43. Furthermore, Nlk reduction ameliorated pathological, behavioral, and lifespan deficits in two distinct mouse models of TDP-43 proteinopathy. Because many toxic proteins can be cleared along the autophagy-lysosome axis, targeted reduction of Nlk represents a potential approach to therapy development for multiple neurodegenerative disorders.

TARDBP

TFEB

LRRK2

10.1172/jci138207

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HnRNP Q Has a Suppressive Role in the Translation of Mouse Cryptochrome1

PLoS ONE (2016)

Ilgye Lim Youngseob Jung Do‐Yeon Kim Kyong‐Tai Kim

Precise regulation of gene expression is especially important for circadian timekeeping which is maintained by the proper oscillation of the mRNA and protein of clock genes and clock-controlled genes. As a main component of the core negative arm feedback loops in the circadian clock, the Cry1 gene contributes to the maintenance of behavioral and molecular rhythmicity. Despite the central role of Cry1, the molecular mechanisms regulating expression levels of Cry1 mRNA and protein are not well defined. In particular, the post-transcriptional regulation of Cry1 mRNA fate decisions is unclear. Here, we demonstrate that hnRNP Q binds to mCry1 mRNA via the 5′UTR. Furthermore, hnRNP Q inhibits the translation of mCry1 mRNA, leading to altered rhythmicity in the mCRY1 protein profile.

10.1371/journal.pone.0159018

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AUF1 contributes to Cryptochrome1 mRNA degradation and rhythmic translation

Nucleic Acids Research (2014)

Kyung‐Ha Lee Sung‐Hoon Kim Hyojin Kim Wanil Kim Hwa‐Rim Lee

Abstract In the present study, we investigated the 3′ untranslated region (UTR) of the mouse core clock gene cryptochrome 1 (Cry1) at the post-transcriptional level, particularly its translational regulation. Interestingly, the 3′UTR of Cry1 mRNA decreased its mRNA levels but increased protein amounts. The 3′UTR is widely known to function as a cis-acting element of mRNA degradation. The 3′UTR also provides a binding site for microRNA and mainly suppresses translation of target mRNAs. We found that AU-rich element RNA binding protein 1 (AUF1) directly binds to the Cry1 3′UTR and regulates translation of Cry1 mRNA. AUF1 interacted with eukaryotic translation initiation factor 3 subunit B and also directly associated with ribosomal protein S3 or ribosomal protein S14, resulting in translation of Cry1 mRNA in a 3′UTR-dependent manner. Expression of cytoplasmic AUF1 and binding of AUF1 to the Cry1 3′UTR were parallel to the circadian CRY1 protein profile. Our results suggest that the 3′UTR of Cry1 is important for its rhythmic translation, and AUF1 bound to the 3′UTR facilitates interaction with the 5′ end of mRNA by interacting with translation initiation factors and recruiting the 40S ribosomal subunit to initiate translation of Cry1 mRNA.

Ribosomal protein

10.1093/nar/gkt1379

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Luteolin Suppresses Cancer Cell Proliferation by Targeting Vaccinia-Related Kinase 1

PLoS ONE (2014)

Ye Seul Kim Seong Hoon Kim Joon Shin Amaravadhi Harikishore Jong-Kwan Lim

Uncontrolled proliferation, a major feature of cancer cells, is often triggered by the malfunction of cell cycle regulators such as protein kinases. Recently, cell cycle-related protein kinases have become attractive targets for anti-cancer therapy, because they play fundamental roles in cellular proliferation. However, the protein kinase-targeted drugs that have been developed so far do not show impressive clinical results and also display severe side effects; therefore, there is undoubtedly a need to investigate new drugs targeting other protein kinases that are critical in cell cycle progression. Vaccinia-related kinase 1 (VRK1) is a mitotic kinase that functions in cell cycle regulation by phosphorylating cell cycle-related substrates such as barrier-to-autointegration factor (BAF), histone H3, and the cAMP response element (CRE)-binding protein (CREB). In our study, we identified luteolin as the inhibitor of VRK1 by screening a small-molecule natural compound library. Here, we evaluated the efficacy of luteolin as a VRK1-targeted inhibitor for developing an effective anti-cancer strategy. We confirmed that luteolin significantly reduces VRK1-mediated phosphorylation of the cell cycle-related substrates BAF and histone H3, and directly interacts with the catalytic domain of VRK1. In addition, luteolin regulates cell cycle progression by modulating VRK1 activity, leading to the suppression of cancer cell proliferation and the induction of apoptosis. Therefore, our study suggests that luteolin-induced VRK1 inhibition may contribute to establish a novel cell cycle-targeted strategy for anti-cancer therapy.

10.1371/journal.pone.0109655

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Citations (43)

Heterogeneous ribonucleoprotein R regulates arylalkylamine N‐acetyltransferase synthesis via internal ribosomal entry site‐mediated translation in a circadian manner

Journal of Pineal Research (2015)

Hwa‐Rim Lee Tae‐Don Kim Hyojin Kim Youngseob Jung Dohyun Lee

Abstract Rhythmic arylalkylamine N‐acetyltransferase ( AANAT ) synthesis is a prominent circadian‐controlled response that occurs in most mammals. AANAT is the core enzyme in melatonin production; because melatonin participates in many physiological processes, the regulation of AANAT is an important research topic. In this study, we focused on the role of heterogeneous ribonucleoprotein R (hn RNP R) in the translation of AANAT . A novel RNA ‐binding protein hn RNP R widely interacted with the 5′ untranslated region ( UTR ) of AANAT m RNA and contributed to translation through an internal ribosomal entry site ( IRES ). Fine‐tuning of AANAT protein synthesis occurred in response to knockdown and overexpression of hn RNP R . Nocturnal elevation of AANAT protein was dependent on the rhythmic changes of hn RNP R , whose levels are elevated in the pineal gland during nighttime. Increases in hn RNP R additionally improved AANAT production in rat pinealocytes under norepinephrine ( NE ) treatment. These results suggest that cap‐independent translation of AANAT m RNA plays a role in the rhythmic synthesis of melatonin through the recruitment of translational machinery to hn RNP R ‐bound AANAT m RNA .

Translational regulation

10.1111/jpi.12284

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Citations (16)

A two-photon fluorescent probe for lysosomal zinc ions

Chemical Communications (2015)

Hyo‐Jun Lee Chang‐Woo Cho Hyewon Seo Subhankar Singha Yong Woong Jun

The selective detection of zinc ions in lysosomes over that in cytosol is achieved with a fluorescent probe, which enabled the fluorescence imaging of endogenous zinc ions in lysosomes of NIH 3T3 cells as well as mouse hippocampal tissues by two-photon microscopy under excitation at 900 nm.

Two-photon excitation microscopy

10.1039/c5cc06976a

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Citations (67)