Identification and Functional Characterization of N-Terminally Acetylated Proteins in Drosophila melanogaster

Goetze, Sandra; Qeli, Ermir; Mosimann, Christian; Staes, An; Gerrits, Bertran; Roschitzki, Bernd; Mohanty, Sonali; Niederer, Eva; Laczkó, Endre; Timmerman, Evy; Lange, Vinzenz; Hafen, Ernst; Aebersold, Ruedi; Vandekerckhove, Joël; Basler, Konrad; Ahrens, Christian H.; Gevaert, Kris; Brunner, Erich

doi:10.1371/journal.pbio.1000236

Cited by 157 publications

(184 citation statements)

References 54 publications

(109 reference statements)

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“…Independently of our work on cathepsin biology, we examined the N-␣ acetylation pattern in order to contribute to recent studies focusing on N-terminal protein acetylation (87)(88)(89)(90)(91)(92)(93). In this context, we present the first proteomic overview of N-␣ acetylation in mice.…”

Section: N-terminal Protein Acetylation Corresponds To Prototypicalmentioning

confidence: 99%

Deletion of Cysteine Cathepsins B or L Yields Differential Impacts on Murine Skin Proteome and Degradome

Tholen

Biniossek

Gansz

et al. 2013

Molecular & Cellular Proteomics

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Numerous studies highlight the fact that concerted proteolysis is essential for skin morphology and function. The cysteine protease cathepsin L (Ctsl) has been implicated in epidermal proliferation and desquamation, as well as in hair cycle regulation. In stark contrast, mice deficient in cathepsin B (Ctsb) do not display an overt skin phenotype. To understand the systematic consequences of deleting Ctsb or Ctsl, we determined the protein abundances of >1300 proteins and proteolytic cleavage events in skin samples of wild-type, Ctsb ؊/؊ , and Ctsl ؊/؊ mice via mass-spectrometry-based proteomics. Both protease deficiencies revealed distinct quantitative changes in proteome composition. Ctsl Cathepsins B and L are ubiquitously expressed papain-like cysteine proteases belonging to the C1a papain family (clan CA), with 11 members in humans (1) and 18 members in mice (2). Most cysteine cathepsins like cathepsin L are endopeptidases, whereas cathepsin B shows both endopeptidase and carboxydipeptidase activity (3). Mainly localized in the endosomal/lysosomal compartment, cathepsins have traditionally been thought to play important roles in lysosomal protein turnover. Additional specific functions have been postulated that link cathepsins to different physiological and pathological processes.Studies using cathepsin L (Ctsl)-gene-deficient mice 1 revealed an important role of Ctsl in cardiac homeostasis (4 -6) and a contribution of Ctsl to MHC II-mediated antigen presentation (7, 8) and prohormone processing (9, 10). In a mouse model of pancreatic neuroendocrine cancer, Ctsl promoted tumor growth and invasiveness (11,12). In stark contrast, Ctsl was found to attenuate tumor progression in mouse models of skin cancer, highlighting the context-specific function of this protease (13,14).The most prominent phenotype of Ctsl-deficient mice is periodic hair loss together with epidermal hyperplasia, acanthosis, and hyperkeratosis (15). These alterations in skin morphology are assumed to be keratinocyte specific, as controlled re-expression of Ctsl under a keratin 14 promoter Research

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Section: N-terminal Protein Acetylation Corresponds To Prototypicalmentioning

confidence: 99%

Deletion of Cysteine Cathepsins B or L Yields Differential Impacts on Murine Skin Proteome and Degradome

Tholen

Biniossek

Gansz

et al. 2013

Molecular & Cellular Proteomics

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show abstract

“…This modification mechanism is used for 60 to 90% of all proteins in eukaryotes (Goetze et al, 2009), and it is conceivable that it also modifies plastid precursor proteins under normal wild-type conditions during their cytosolic synthesis and transition. The sequence context around the identified N-acetylation sites is consistent with described requirements for this type of modification (i.e., small, uncharged residues like Ala follow the start Met) (Sherman et al, 1985;Meinnel et al, 2006).…”

Section: N-terminal Met Excision and Acetylation Of Plastid Precursormentioning

confidence: 99%

“…Following transit peptide removal, the newly generated protein N terminus may be acetylated (Ferro et al, 2003;Kleffmann et al, 2007;Zybailov et al, 2008). N-acetylation is catalyzed by N-terminal acetyltransferases in the cytosol and in the plastid (Sherman et al, 1985;Meinnel et al, 2006;Goetze et al, 2009). It is therefore possible that a chloroplast-targeted protein may be acetylated as a precursor in the cytosol and after import and processing as the mature protein.…”

Section: Introductionmentioning

confidence: 99%

Plastid Proteome Assembly without Toc159: Photosynthetic Protein Import and Accumulation of N-Acetylated Plastid Precursor Proteins

et al. 2011

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Import of nuclear-encoded precursor proteins from the cytosol is an essential step in chloroplast biogenesis that is mediated by protein translocon complexes at the inner and outer envelope membrane (TOC). Toc159 is thought to be the main receptor for photosynthetic proteins, but lacking a large-scale systems approach, this hypothesis has only been tested for a handful of photosynthetic and nonphotosynthetic proteins. To assess Toc159 precursor specificity, we quantitatively analyzed the accumulation of plastid proteins in two mutant lines deficient in this receptor. Parallel genomewide transcript profiling allowed us to discern the consequences of impaired protein import from systemic transcriptional responses that contribute to the loss of photosynthetic capacity. On this basis, we defined putative Toc159-independent and Toc159-dependent precursor proteins. Many photosynthetic proteins accumulate in Toc159-deficient plastids, and, surprisingly, several distinct metabolic pathways are negatively affected by Toc159 depletion. Lack of Toc159 furthermore affects several proteins that accumulate as unprocessed N-acetylated precursor proteins outside of plastids. Together, our data show an unexpected client protein promiscuity of Toc159 that requires a far more differentiated view of Toc159 receptor function and regulation of plastid protein import, in which cytosolic Met removal followed by N-terminal acetylation of precursors emerges as an additional regulatory step.

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“…In eukaryotes, cotranslational N-terminal Met excision (NME) by Met aminopeptidases (MetAP) and N-aterminal acetylation (Nt-acetylation) catalyzed by N-terminal acetyltransferases (Nats) are two major protein modifications contributing to the diversity of protein N termini and to the N-end rule (Giglione et al, 2000(Giglione et al, , 2003Ross et al, 2005;Frottin et al, 2009;Gibbs et al, 2014a). Although limited studies have been conducted in plants on the N-end rule (Giglione et al, 2003;Graciet et al, 2009;Holman et al, 2009;Adam et al, 2011;Bienvenut et al, 2011;Gibbs et al, 2011Gibbs et al, , 2014bLicausi et al, 2011;Weits et al, 2014), recent genomic and N-terminal acetylome analyses in yeast, animals, and plants revealed that the NME and Nt-acetylation processes, along with the related enzymatic activities, are largely conserved through eukaryotic lineages (Polevoda et al, 1999;Arnesen et al, 2009;Goetze et al, 2009;Bienvenut et al, 2012;Liu et al, 2013). Particularly, in vivo and in vitro studies have shown that all MetAPs share similar substrate specificity, removing the first Met only when the second residue has a small radius of gyration of the side chain; on the contrary, bulky amino acids do not allow the removal of the first Met (Bienvenut et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Two N-Terminal Acetyltransferases Antagonistically Regulate the Stability of a Nod-Like Receptor in Arabidopsis

et al. 2015

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Nod-like receptors (NLRs) serve as immune receptors in plants and animals. The stability of NLRs is tightly regulated, though its mechanism is not well understood. Here, we show the crucial impact of N-terminal acetylation on the turnover of one plant NLR, Suppressor of NPR1, Constitutive 1 (SNC1), in Arabidopsis thaliana. Genetic and biochemical analyses of SNC1 uncovered its multilayered regulation by different N-terminal acetyltransferase (Nat) complexes. SNC1 exhibits a few distinct N-terminal isoforms generated through alternative initiation and N-terminal acetylation. Its first Met is acetylated by N-terminal acetyltransferase complex A (NatA), while the second Met is acetylated by N-terminal acetyltransferase complex B (NatB). Unexpectedly, the NatAmediated acetylation serves as a degradation signal, while NatB-mediated acetylation stabilizes the NLR protein, thus revealing antagonistic N-terminal acetylation of a single protein substrate. Moreover, NatA also contributes to the turnover of another NLR, RESISTANCE TO P. syringae pv maculicola 1. The intricate regulation of protein stability by Nats is speculated to provide flexibility for the target protein in maintaining its homeostasis.

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Identification and Functional Characterization of N-Terminally Acetylated Proteins in Drosophila melanogaster

Abstract: A new study reveals a functional rule for N-terminal acetylation in higher eukaryotes called the (X)PX rule and describes a generic method that prevents this modification to allow the study of N-terminal acetylation in any given protein.

Cited by 157 publications

References 54 publications

Deletion of Cysteine Cathepsins B or L Yields Differential Impacts on Murine Skin Proteome and Degradome

Deletion of Cysteine Cathepsins B or L Yields Differential Impacts on Murine Skin Proteome and Degradome

Plastid Proteome Assembly without Toc159: Photosynthetic Protein Import and Accumulation of N-Acetylated Plastid Precursor Proteins

Two N-Terminal Acetyltransferases Antagonistically Regulate the Stability of a Nod-Like Receptor in Arabidopsis

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