Dataset Information

The Neuron-Specific Protein TMEM59L Mediates Oxidative Stress-Induced Cell Death.

ABSTRACT: TMEM59L is a newly identified brain-specific membrane-anchored protein with unknown functions. Herein we found that both TMEM59L and its homolog, TMEM59, are localized in Golgi and endosomes. However, in contrast to a ubiquitous and relatively stable temporal expression of TMEM59, TMEM59L expression was limited in neurons and increased during development. We also found that both TMEM59L and TMEM59 interacted with ATG5 and ATG16L1, and that overexpression of them triggered cell autophagy. However, overexpression of TMEM59L induced intrinsic caspase-dependent apoptosis more dramatically than TMEM59. In addition, downregulation of TMEM59L prevented neuronal cell death and caspase-3 activation caused by hydrogen peroxide insults and reduced the lipidation of LC3B. Finally, we found that AAV-mediated knockdown of TMEM59L in mice significantly ameliorated caspase-3 activation, increased mouse duration in the open arm during elevated plus maze test, reduced mouse immobility time during forced swim test, and enhanced mouse memory during Y-maze and Morris water maze tests. Together, our study indicates that TMEM59L is a pro-apoptotic neuronal protein involved in animal behaviors such as anxiety, depression, and memory, and that TMEM59L downregulation protects neurons against oxidative stress.

SUBMITTER: Zheng Q

PROVIDER: S-EPMC5288309 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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The Neuron-Specific Protein TMEM59L Mediates Oxidative Stress-Induced Cell Death.

Zheng Qiuyang Q Zheng Xiaoyuan X Zhang Lishan L Luo Hong H Qian Lingzhi L Fu Xing X Liu Yiqian Y Gao Yuehong Y Niu Mengxi M Meng Jian J Zhang Muxian M Bu Guojun G Xu Huaxi H Zhang Yun-Wu YW

Molecular neurobiology 20160621 6

TMEM59L is a newly identified brain-specific membrane-anchored protein with unknown functions. Herein we found that both TMEM59L and its homolog, TMEM59, are localized in Golgi and endosomes. However, in contrast to a ubiquitous and relatively stable temporal expression of TMEM59, TMEM59L expression was limited in neurons and increased during development. We also found that both TMEM59L and TMEM59 interacted with ATG5 and ATG16L1, and that overexpression of them triggered cell autophagy. However ...[more]

PMID: 27324899

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Project description:We previously demonstrated that protein kinase C? (PKC?; PKC delta) is an oxidative stress-sensitive kinase that plays a causal role in apoptotic cell death in neuronal cells. Although PKC? activation has been extensively studied, relatively little is known about the molecular mechanisms controlling PKC? expression. To characterize the regulation of PKC? expression, we cloned an ?2-kbp 5'-promoter segment of the mouse Prkcd gene. Deletion analysis indicated that the noncoding exon 1 region contained multiple Sp sites, including four GC boxes and one CACCC box, which directed the highest levels of transcription in neuronal cells. In addition, an upstream regulatory region containing adjacent repressive and anti-repressive elements with opposing regulatory activities was identified within the region -712 to -560. Detailed mutagenesis studies revealed that each Sp site made a positive contribution to PKC? promoter expression. Overexpression of Sp family proteins markedly stimulated PKC? promoter activity without any synergistic transactivating effect. Furthermore, experiments in Sp-deficient SL2 cells indicated long isoform Sp3 as the essential activator of PKC? transcription. Importantly, both PKC? promoter activity and endogenous PKC? expression in NIE115 cells and primary striatal cultures were inhibited by mithramycin A. The results from chromatin immunoprecipitation and gel shift assays further confirmed the functional binding of Sp proteins to the PKC? promoter. Additionally, we demonstrated that overexpression of p300 or CREB-binding protein increases the PKC? promoter activity. This stimulatory effect requires intact Sp-binding sites and is independent of p300 histone acetyltransferase activity. Finally, modulation of Sp transcriptional activity or protein level profoundly altered the cell death induced by oxidative insult, demonstrating the functional significance of Sp-dependent PKC? gene expression. Collectively, our findings may have implications for development of new translational strategies against oxidative damage.

Dataset Information

The Neuron-Specific Protein TMEM59L Mediates Oxidative Stress-Induced Cell Death.

Publications

The Neuron-Specific Protein TMEM59L Mediates Oxidative Stress-Induced Cell Death.

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