GADD34 is a modulator of autophagy during starvation

Gambardella, Gennaro; Staiano, Leopoldo; Moretti, Maria Nicoletta; Cegli, Rossella De; Fagnocchi, Luca; Tullio, Giuseppe Di; Polletti, Sara; Braccia, Clarissa; Armirotti, Andrea; Zippo, Alessio; Ballabio, Andrea; Matteis, Maria Antonietta De; Bernardo, Diego di

doi:10.1126/sciadv.abb0205

Cited by 46 publications

(40 citation statements)

References 45 publications

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“…The PPP1R15A gene mediated cell growth arrest and apoptosis in response to DNA damage (Wu et al, 2002). It has shown its induced effect on autophagy through the suppression of the mTOR pathway during starvation (Uddin et al, 2011;Gambardella et al, 2020). We did not find any effects of this gene on testicular function in the literature.…”

Section: Discussionmentioning

confidence: 66%

Whole-Exome Sequencing Analysis of Human Semen Quality in Russian Multiethnic Population

et al. 2021

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The global trend toward the reduction of human spermatogenic function observed in many countries, including Russia, raised the problem of extensive screening and monitoring of male fertility and elucidation of its genetic and ethnic mechanisms. Recently, whole-exome sequencing (WES) was developed as a powerful tool for genetic analysis of complex traits. We present here the first Russian WES study for identification of new genes associated with semen quality. The experimental 3 × 2 design of the WES study was based on the analysis of 157 samples including three ethnic groups—Slavs (59), Buryats (n = 49), and Yakuts (n = 49), and two different semen quality groups—pathozoospermia (n = 95) and normospermia (n = 62). Additionally, our WES study group was negative for complete AZF microdeletions of the Y-chromosome. The normospermia group included men with normal sperm parameters in accordance with the WHO-recommended reference limit. The pathozoospermia group included men with impaired semen quality, namely, with any combined parameters of sperm concentration <15 × 106/ml, and/or progressive motility <32%, and/or normal morphology <4%. The WES was performed for all 157 samples. Subsequent calling and filtering of variants were carried out according to the GATK Best Practices recommendations. On the genotyping stage, the samples were combined into four cohorts: three sets corresponded to three ethnic groups, and the fourth set contained all the 157 whole-exome samples. Association of the obtained polymorphisms with semen quality parameters was investigated using the χ2 test. To prioritize the obtained variants associated with pathozoospermia, their effects were determined using Ensembl Variant Effect Predictor. Moreover, polymorphisms located in genes expressed in the testis were revealed based on the genomic annotation. As a result, the nine potential SNP markers rs6971091, rs557806, rs610308, rs556052, rs1289658, rs278981, rs1129172, rs12268007, and rs17228441 were selected for subsequent verification on our previously collected population sample (about 1,500 males). The selected variants located in seven genes FAM71F1, PPP1R15A, TRIM45, PRAME, RBM47, WDFY4, and FSIP2 that are expressed in the testis and play an important role in cell proliferation, meiosis, and apoptosis.

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Section: Discussionmentioning

confidence: 66%

Whole-Exome Sequencing Analysis of Human Semen Quality in Russian Multiethnic Population

et al. 2021

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“…In addition, PERK-mediated ATF4/CHOP expression induces autophagy by inhibiting mTORC1 activity ( Salazar et al, 2009 ; Bruning et al, 2013 ). Recently, The TFEB-mediated GADD34 expression may integrate mTORC1-mediated autophagy and ER stress ( Gambardella et al, 2020 ). ER stress can also activate the CMA pathway by PERK activation, which recruits mitogen-activated protein kinase 4 (MKK4) and activates p38 to phosphorylate LAMP2A for CMA activation ( Li et al, 2017 ).…”

Section: Interplay Of Er Stress and Autophagymentioning

confidence: 99%

The Cross-Links of Endoplasmic Reticulum Stress, Autophagy, and Neurodegeneration in Parkinson’s Disease

Ren

Zhai

et al. 2021

Front. Aging Neurosci.

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Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, and it is characterized by the selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), as well as the presence of intracellular inclusions with α-synuclein as the main component in surviving DA neurons. Emerging evidence suggests that the imbalance of proteostasis is a key pathogenic factor for PD. Endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) and autophagy, two major pathways for maintaining proteostasis, play important roles in PD pathology and are considered as attractive therapeutic targets for PD treatment. However, although ER stress/UPR and autophagy appear to be independent cellular processes, they are closely related to each other. In this review, we focused on the roles and molecular cross-links between ER stress/UPR and autophagy in PD pathology. We systematically reviewed and summarized the most recent advances in regulation of ER stress/UPR and autophagy, and their cross-linking mechanisms. We also reviewed and discussed the mechanisms of the coexisting ER stress/UPR activation and dysregulated autophagy in the lesion regions of PD patients, and the underlying roles and molecular crosslinks between ER stress/UPR activation and the dysregulated autophagy in DA neurodegeneration induced by PD-associated genetic factors and PD-related neurotoxins. Finally, we indicate that the combined regulation of ER stress/UPR and autophagy would be a more effective treatment for PD rather than regulating one of these conditions alone.

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“…PPP1R15A is involved in apoptosis following ionizing radiation [ 59 ], methyl-methanesulfonate treatments [ 60 ], and in endoplasmic reticulum stress [ 58 ]. In 2020, Gambardella et al [ 61 ] found that PPP1R15A also plays an essential role in autophagy, by enabling lysosomal biogenesis and a sustained autophagic flux [ 61 ]. In fact, PPP1R15A is also essential for translation during starvation [ 61 ] but also in apoptosis, if the endoplasmic reticulum stress is not resolved [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

“…In 2020, Gambardella et al [ 61 ] found that PPP1R15A also plays an essential role in autophagy, by enabling lysosomal biogenesis and a sustained autophagic flux [ 61 ]. In fact, PPP1R15A is also essential for translation during starvation [ 61 ] but also in apoptosis, if the endoplasmic reticulum stress is not resolved [ 62 ]. Therefore, PPP1R15A plays a crucial role in both autophagy and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Potential Genes Involved in Cancer by Integrated Comparative Analyses

Monticolo

Palomba

Chiusano

2020

IJMS

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The main hallmarks of cancer diseases are the evasion of programmed cell death, uncontrolled cell division, and the ability to invade adjacent tissues. The explosion of omics technologies offers challenging opportunities to identify molecular agents and processes that may play relevant roles in cancer. They can support comparative investigations, in one or multiple experiments, exploiting evidence from one or multiple species. Here, we analyzed gene expression data from induction of programmed cell death and stress response in Homo sapiens and compared the results with Saccharomyces cerevisiae gene expression during the response to cell death. The aim was to identify conserved candidate genes associated with Homo sapiens cell death, favored by crosslinks based on orthology relationships between the two species. We identified differentially-expressed genes, pathways that are significantly dysregulated across treatments, and characterized genes among those involved in induced cell death. We investigated on co-expression patterns and identified novel genes that were not expected to be associated with death pathways, that have a conserved pattern of expression between the two species. Finally, we analyzed the resulting list by HumanNet and identified new genes predicted to be involved in cancer. The data integration and the comparative approach between distantly-related reference species that were here exploited pave the way to novel discoveries in cancer therapy and also contribute to detect conserved genes potentially involved in programmed cell death.

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GADD34 is a modulator of autophagy during starvation

Cited by 46 publications

References 45 publications

Whole-Exome Sequencing Analysis of Human Semen Quality in Russian Multiethnic Population

Whole-Exome Sequencing Analysis of Human Semen Quality in Russian Multiethnic Population

The Cross-Links of Endoplasmic Reticulum Stress, Autophagy, and Neurodegeneration in Parkinson’s Disease

Identification of Novel Potential Genes Involved in Cancer by Integrated Comparative Analyses

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