Neddylation modification of ribosomal protein RPS27L or RPS27 by MDM2 or NEDP1 regulates cancer cell survival

Xiong, Xiufang; Cui, Di; Bi, Yanli; Sun, Yi; Zhao, Yongchao

doi:10.1096/fj.202000530rrr

Cited by 12 publications

(5 citation statements)

References 32 publications

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“…From previous literature, some evidence may suggest that eS27 and eS27L do have distinct protein functions, especially in p53-related signaling pathways and apoptotic processes resulting from genotoxic stimuli (He & Sun, 2007;Li et al, 2007;Xiong et al, 2018Xiong et al, , 2020Zhao et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Subfunctionalized expression drives evolutionary retention of ribosomal protein paralogs in vertebrates

Molinuevo

Fazzari

et al. 2022

Preprint

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The formation of paralogs through gene duplication is a core evolutionary process. For paralogs that encode components of protein complexes such as the ribosome, a central question is whether they encode functionally distinct proteins, or whether they exist to maintain appropriate total expression of equivalent proteins. Here, we systematically tested evolutionary models of paralog function using the mammalian ribosomal protein paralogs eS27 (Rps27) and eS27L (Rps27l) as a case study. We first showed that eS27 and eS27L have inversely correlated mRNA abundance across cell types, with the highest eS27 in lymphocytes and the highest eS27L in mammary alveolar cells and hepatocytes. By endogenously tagging the eS27 and eS27L proteins, we demonstrated that eS27- and eS27L- ribosomes associate preferentially with different transcripts. Furthermore, we generated murine eS27 and eS27L loss-of-function alleles that are homozygous lethal at different developmental stages. However, strikingly, we found that expressing eS27 protein from the endogenous eS27L locus, or vice versa, completely rescues loss-of-function lethality and yields mice with no detectable deficits. Together, these findings suggest that eS27 and eS27L are evolutionarily retained because their subfunctionalized expression patterns render both genes necessary to achieve the requisite total expression of two equivalent proteins across cell types. Our work represents the most in-depth characterization of a mammalian ribosomal protein paralog to date and highlights the importance of considering both protein function and expression when investigating paralogs.

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Section: Discussionmentioning

confidence: 99%

Subfunctionalized expression drives evolutionary retention of ribosomal protein paralogs in vertebrates

Molinuevo

Fazzari

et al. 2022

Preprint

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“…This process was controlled by Myeov2, which can reverse L11 NEDDylation changing the nuclear localization of L11, allowing L11 to localize outside of the nucleus and regulate p53 activity [55]. MDM2 has also been shown to NEDDylate the ribosomal proteins RPS27and RPS27L which conferred stability to the protein and promoted cancer cell survival [56]. Recent work has provided some significant clues as to how and why ribosomal proteins may be the target of NEDD8 modification, especially during periods of stress to the cell.…”

Section: Ribosomal Protein Neddylationmentioning

confidence: 99%

The Many Potential Fates of Non-Canonical Protein Substrates Subject to NEDDylation

Vijayasimha

Dolan

2021

Cells

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Neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) is a ubiquitin-like protein (UBL) whose canonical function involves binding to, and thus, activating Cullin–Ring finger Ligases (CRLs), one of the largest family of ubiquitin ligases in the eukaryotic cell. However, in recent years, several non-canonical protein substrates of NEDD8 have been identified. Here we attempt to review the recent literature regarding non-canonical NEDDylation of substrates with a particular focus on how the covalent modification of NEDD8 alters the protein substrate. Like much in the study of ubiquitin and UBLs, there are no clear and all-encompassing explanations to satisfy the textbooks. In some instances, NEDD8 modification appears to alter the substrates localization, particularly during times of stress. NEDDylation may also have conflicting impacts upon a protein’s stability: some reports indicate NEDDylation may protect against degradation whereas others show NEDDylation can promote degradation. We also examine how many of the in vitro studies measuring non-canonical NEDDylation were conducted and compare those conditions to those which may occur in vivo, such as cancer progression. It is likely that the conditions used to study non-canonical NEDDylation are similar to some types of cancers, such as glioblastoma, colon and rectal cancers, and lung adenocarcinomas. Although the full outcomes of non-canonical NEDDylation remain unknown, our review of the literature suggests that researchers keep an open mind to the situations where this modification occurs and determine the functional impacts of NEDD8-modification to the specific substrates which they study.

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“…In addition to cullins, a growing list of proteins have been identified as NEDD8 targets. These include Parkin, PINK1, HIF1α, TGFβRII, MDM2, p53, p73, VHL ( Wolf et al, 2020 ), RPS27L, RPS27 ( Xiong et al, 2020 ) and COFILIN ( Vogl et al, 2020 ), among others [also see reviews ( Kandala et al, 2014 ; Enchev et al, 2015 )]. Insights gained from characterizations of these new NEDD8 substrates have expanded our understanding of neddylation in diverse cellular pathways.…”

Section: Proteome-wide Identification Of Nedd8 Targetsmentioning

confidence: 99%

“…For instance, PPARγ, a crucial player in the regulation of lipid and glucose metabolism, can be modified at unknown lysine sites, which increases its stability by preventing ubiquitination ( Park et al, 2016 ). Similarly, neddylation of other proteins, including the ribosomal proteins RPS27L and RPS27, mitochondrial proteins ETFA and ETFB, and lipogenic transcription factor SREBP1, also increases their stability ( Heo et al, 2020 ; Xiong et al, 2020 ; Zhang X. et al, 2020 ).…”

Section: Molecular Actions Of Neddylationmentioning

confidence: 99%

Neddylation, an Emerging Mechanism Regulating Cardiac Development and Function

Zou

Littlejohn

et al. 2020

Front. Physiol.

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Defects in protein quality control have been increasingly recognized as pathogenic factors in the development of heart failure, a persistent devastating disease lacking efficacious therapies. Ubiquitin and ubiquitin-like proteins, a family of post-translational modifying polypeptides, play important roles in controlling protein quality by maintaining the stability and functional diversity of the proteome. NEDD8 (neural precursor cell expressed, developmentally downregulated 8), a small ubiquitin-like protein, was discovered two decades ago but until recently the biological significance of NEDD8 modifications (neddylation) in the heart has not been appreciated. In this review, we summarize the current knowledge of the biology of neddylation, highlighting several mechanisms by which neddylation regulates the function of its downstream targets, and discuss the expanding roles for neddylation in cardiac physiology and disease, with an emphasis on cardiac protein quality control. Finally, we outline challenges linked to the study of neddylation in health and disease.

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Neddylation modification of ribosomal protein RPS27L or RPS27 by MDM2 or NEDP1 regulates cancer cell survival

Cited by 12 publications

References 32 publications

Subfunctionalized expression drives evolutionary retention of ribosomal protein paralogs in vertebrates

Subfunctionalized expression drives evolutionary retention of ribosomal protein paralogs in vertebrates

The Many Potential Fates of Non-Canonical Protein Substrates Subject to NEDDylation

Neddylation, an Emerging Mechanism Regulating Cardiac Development and Function

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