Control of protein degradation by N-terminal acetylation and the N-end rule pathway

Mun, Sang-Hyeon; Lee, Chang-Suck; Hwang, Cheol-Sang

doi:10.1038/s12276-018-0097-y

Cited by 86 publications

(60 citation statements)

References 82 publications

(126 reference statements)

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“…Under lipid-rich conditions, PLIN2 contacts directly with neutral lipids and retains a SNARE complex protein, SNAP23, on the LD via their augmented interaction (38). Considering the degradation of free PLIN2 by the UPS in the cytosol, such lipid or protein bindings most likely induce its conformational change and, subsequently, shield the Ac/N-degron, thus protecting the PLIN2 protein from destruction by the TEB4-mediated Ac/N-end rule pathway, in agreement with the conditionality of Ac/N-degrons demonstrated in our previous works (12,17,18). Another plausible explanation for the stabilization of PLIN2 on LD most likely stems from the spatial segregation between LD-anchored PLIN2 and ER-embedded TEB4, which would prevent the interaction of the Ac/N-degron of PLIN2 with TEB4 E3 Ub ligase.…”

Section: Discussionsupporting

confidence: 90%

“…7). In addition, it is noteworthy that A-PLIN2 is the first example of a NatA-dependent substrate of the Ac/N-end rule pathway to be identified in mammals, although the NatA complex acetylates 30 -40% of the N termini in the human proteome (12,27).…”

Section: Discussionmentioning

confidence: 99%

“…Nt-Asn, Gln, or Cys may be destabilized after preliminary modifications (Nt-deamidation, arginylation, and Cys-oxidation, respectively). Another N-end rule pathway is the Pro/N-end rule pathway in which a Pro/N-recognin GID4 E3 Ub ligase is recruited to target unmodified Nt-Pro residues for degradation of the protein (12,14,15).…”

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confidence: 99%

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N-terminal acetylation and the N-end rule pathway control degradation of the lipid droplet protein PLIN2

Nguyen

Lee

Mun

et al. 2019

Journal of Biological Chemistry

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Perilipin 2 (PLIN2) is a major lipid droplet (LD)-associated protein that regulates intracellular lipid homeostasis and LD formation. Under lipid-deprived conditions, the LD-unbound (free) form of PLIN2 is eliminated in the cytosol by an as yet unknown ubiquitin (Ub)-proteasome pathway that is associated with the N-terminal or near N-terminal residues of the protein.Here, using HeLa, HEK293T, and HepG2 human cell lines, cycloheximide chase, in vivo ubiquitylation, split-Ub yeast twohybrid, and chemical cross-linking-based reciprocal co-immunoprecipitation assays, we found that TEB4 (MARCH6), an E3 Ub ligase and recognition component of the Ac/N-end rule pathway, directly targets the N-terminal acetyl moiety of N␣-terminally acetylated PLIN2 for its polyubiquitylation and degradation by the 26S proteasome. We also show that the TEB4-mediated Ac/N-end rule pathway reduces intracellular LD accumulation by degrading PLIN2. Collectively, these findings identify PLIN2 as a substrate of the Ac/N-end rule pathway and indicate a previously unappreciated role of the Ac/N-end rule pathway in LD metabolism.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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N-terminal acetylation and the N-end rule pathway control degradation of the lipid droplet protein PLIN2

Nguyen

Lee

Mun

et al. 2019

Journal of Biological Chemistry

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“…A less well-studied modification, N-terminal (Nt-) acetylation, has been described on PA-X ( Fig 1A). Nt-acetylation occurs cotranslationally on 80% of all proteins and may play roles in subcellular localization, protein stability, and protein-protein interactions (reviewed in [46]). A recent report revealed that PA-X Nt-acetylation is required for its activity [47].…”

Section: Co-and Posttranslational Modification Of Host Shutoff Rnasesmentioning

confidence: 99%

Fine-tuning a blunt tool: Regulation of viral host shutoff RNases

2020

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The evolutionary arms race between host and pathogen has resulted in the ability of many human viruses to alter the host gene expression profile during infection, in order to redirect cellular resources towards viral gene expression and inhibit cell-intrinsic host immune responses. In particular, multiple viruses globally reduce host gene expression in a process termed "host shutoff." Multiple mechanisms of host shutoff exist, including translational and transcriptional shutoff, but several viruses carry out host shutoff by encoding ribonucleases (RNases) that degrade host messenger RNAs (mRNAs). Viral host shutoff RNases include the influenza A virus polymerase acidic-X (PA-X) [1], the herpes simplex viruses (HSV-1 and -2) virion host shutoff protein (vhs) [2], and the Kaposi's sarcoma-associated herpesvirus (KSHV) shutoff and exonuclease (SOX) protein [3] and its homologs, muSOX from murine gammaherpesvirus 68 (MHV68) [4] and BGLF5 from Epstein-Barr virus (EBV) [5]. These RNases contribute to efficient formation of virions and/or reduction of innate immune signaling [6][7][8]. For example, in the absence of EBV BGLF5, the virus produces fewer mature capsids, many of which remain trapped in the nucleus [7]. Vhs-deficient HSV replicates well in many common tissue culture models [9] but shows replication defects in relevant cell types, such as cerebellar granule neurons [8]. Moreover, in mice, viruses lacking detectable host shutoff activity replicate to lower viral titers in neuronal tissue [9], indicating a restriction of viral replication probably related to host immune responses. Influenza A virus PA-X also limits host antiviral and proinflammatory responses in several animal models [1,10,11] but has minimal effect on viral replication both in vivo and in cell culture [1,11,12]. Although host shutoff RNases are important for successful viral infection, their activity presents an interesting problem for the viruses that encode them. Unregulated RNase activity could degrade viral RNAs or host mRNAs encoding proteins that the virus needs. Moreover, drastic depletion of the mRNA pool by the virus could trigger antiviral host stress responses and cell death. It is thus unsurprising that evidence is now emerging that viruses posttranslationally regulate the activity of their host shutoff RNases through a variety of mechanisms, reviewed herein (Fig 1), to finetune host gene regulation without inhibiting viral replication. Selection of targeted and protected RNAs and protein/protein interactionsAll host shutoff RNases cause global decreases in host mRNA abundance, revealed by transcriptome-wide studies [13][14][15], and display a preference for mRNAs while sparing housekeeping noncoding RNAs (ncRNAs) [12,16,17]. However, host shutoff RNases are less PLOS PATHOGENS PLOS Pathogens | https://doi.

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“…methionine aminopeptidases 1 and 2 (MAP1/2), which, in the absence of Nt-acetylation, can remove the initiator methionine (iMet) form the nascent chain. This leads to the exposure of the second residue, which in the case of NatB and NatC N-termini will lead to the exposure of an Arg/N-degron that can targets the protein for Ubr1 dependent degradation (Kats et al, 2018;Nguyen et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of up-regulation of Ubiquitin-Proteasome activity in the absence of NatA dependent N-terminal acetylation

Kats

Kschonsak

Khmelinskii³

et al. 2020

Preprint

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N-terminal acetylation is a prominent protein modification and inactivation of N-terminal acetyltransferases (NATs) cause protein homeostasis stress. Using multiplexed protein stability (MPS) profiling with linear ubiquitin fusions as reporters for the activity of the ubiquitin proteasome system (UPS) we observed increased UPS activity in NatA, but not NatB or NatC mutants. We find several mechanisms contributing to this behavior. First, NatA-mediated acetylation of the N-terminal ubiquitin independent degron regulates the abundance of Rpn4, the master regulator of the expression of proteasomal genes. Second, the abundance of several E3 ligases involved in degradation of UFD substrates is increased in cells lacking NatA. Finally, we identify the E3 ligase Tom1 as a novel chain elongating enzyme (E4) involved in the degradation of linear ubiquitin fusions via the formation of branched K11 and K29 ubiquitin chains, independently of the known E4 ligases involved in UFD, leading to enhanced ubiquitination of the UFD substrates.

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Control of protein degradation by N-terminal acetylation and the N-end rule pathway

Cited by 86 publications

References 82 publications

N-terminal acetylation and the N-end rule pathway control degradation of the lipid droplet protein PLIN2

N-terminal acetylation and the N-end rule pathway control degradation of the lipid droplet protein PLIN2

Fine-tuning a blunt tool: Regulation of viral host shutoff RNases

Mechanisms of up-regulation of Ubiquitin-Proteasome activity in the absence of NatA dependent N-terminal acetylation

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