Naa12 compensates for Naa10 in mice in the amino-terminal acetylation pathway
- Ewha Womans University, Republic of Korea
- Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, United States
- Perelman School of Medicine, University of Pennsylvania, United States
- University of Bergen, Norway
- Department of Molecular Biology, New York State Institute for Basic Research in Developmental Disabilities, United States
- New York State Institute for Basic Research in Developmental Disabilities, United States
- Washington University School of Medicine, United States
- Korea Institute of Science and Technology, Republic of Korea
- Indiana University School of Medicine, United States
- Pohang University of Science and Technology, Republic of Korea
- George A Jervis Clinic, New York State Institute for Basic Research in Developmental Disabilities, United States
Abstract
Amino-terminal acetylation is catalyzed by a set of N-terminal acetyltransferases (NATs). The NatA complex (including X-linked Naa10 and Naa15) is the major acetyltransferase, with 40-50% of all mammalian proteins being potential substrates. However, the overall role of amino-terminal acetylation on a whole-organism level is poorly understood, particularly in mammals. Male mice lacking Naa10 show no globally apparent in vivo amino-terminal acetylation impairment and do not exhibit complete embryonic lethality. Rather Naa10 nulls display increased neonatal lethality, and the majority of surviving undersized mutants exhibit a combination of hydrocephaly, cardiac defects, homeotic anterior transformation, piebaldism and urogenital anomalies. Naa12 is a previously unannotated Naa10-like paralogue with NAT activity that genetically compensates for Naa10. Mice deficient for Naa12 have no apparent phenotype, whereas mice deficient for Naa10 and Naa12 display embryonic lethality. The discovery of Naa12 adds to the currently known machinery involved in amino-terminal acetylation in mice.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.Mass spectrometry data were uploaded to PRIDE under Project Name: Naa10 mutant mouse N-terminome LC-MS, Project accession: PXD026410.
Article and author information
Author details
Funding
National Research Foundation of Korea (2020R1A3B2079811)
- Gootaeg Oh
Norwegian Cancer Society (PR-2009-0222)
- Thomas Arnesen
National Research Foundation of Korea (2017RIDIAB03032286)
- Mi-Ni Lee
National Research Foundation of Korea (2020RICIC1007686)
- Mi-Ni Lee
National Institute of General Medical Sciences (R35GM133408)
- Gholson J Lyon
National Institute of General Medical Sciences (R35GM118090)
- Ronen Marmorstein
Research Council of Norway (Project 249843)
- Thomas Arnesen
National Institutes of Health (Project 249843)
- Simon J Conway
Norwegian Health Authorities of Western Norway (912176)
- Thomas Arnesen
Norwegian Health Authorities of Western Norway (F-12540-D11382)
- Thomas Arnesen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Hening Lin, Cornell University, United States
Ethics
Animal experimentation: All experiments were performed in accordance with guidelines of International Animal Care and Use Committee (IACUC) of Ewha Womans University (protocol #18 012)012), Cold Spring Harbor L aboratory (CSHL) protocol # 579961 18 , and Institute for Basic Research in Developmental Disabilities (IBR) (protocol #456).
Version history
- Preprint posted: December 20, 2020 (view preprint)
- Received: December 20, 2020
- Accepted: August 5, 2021
- Accepted Manuscript published: August 6, 2021 (version 1)
- Accepted Manuscript updated: August 11, 2021 (version 2)
- Version of Record published: August 19, 2021 (version 3)
Copyright
© 2021, Kweon et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,252
- views
-
- 167
- downloads
-
- 8
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Naa12 compensates for Naa10 in mice in the amino-terminal acetylation pathway
eLife 10:e65952.
https://doi.org/10.7554/eLife.65952
Further reading
-
- Developmental Biology
- Structural Biology and Molecular Biophysics
The receptor tyrosine kinase ROR2 mediates noncanonical WNT5A signaling to orchestrate tissue morphogenetic processes, and dysfunction of the pathway causes Robinow syndrome, brachydactyly B, and metastatic diseases. The domain(s) and mechanisms required for ROR2 function, however, remain unclear. We solved the crystal structure of the extracellular cysteine-rich (CRD) and Kringle (Kr) domains of ROR2 and found that, unlike other CRDs, the ROR2 CRD lacks the signature hydrophobic pocket that binds lipids/lipid-modified proteins, such as WNTs, suggesting a novel mechanism of ligand reception. Functionally, we showed that the ROR2 CRD, but not other domains, is required and minimally sufficient to promote WNT5A signaling, and Robinow mutations in the CRD and the adjacent Kr impair ROR2 secretion and function. Moreover, using function-activating and -perturbing antibodies against the Frizzled (FZ) family of WNT receptors, we demonstrate the involvement of FZ in WNT5A-ROR signaling. Thus, ROR2 acts via its CRD to potentiate the function of a receptor super-complex that includes FZ to transduce WNT5A signals.
-
- Cell Biology
- Developmental Biology
The generation of distinct cell fates during development depends on asymmetric cell division of progenitor cells. In the central and peripheral nervous system of Drosophila, progenitor cells respectively called neuroblasts or sensory organ precursors use PAR polarity during mitosis to control cell fate determination in their daughter cells. How polarity and the cell cycle are coupled, and how the cell cycle machinery regulates PAR protein function and cell fate determination is poorly understood. Here, we generate an analog sensitive allele of CDK1 and reveal that its partial inhibition weakens but does not abolish apical polarity in embryonic and larval neuroblasts and leads to defects in polarisation of fate determinants. We describe a novel in vivo phosphorylation of Bazooka, the Drosophila homolog of PAR-3, on Serine180, a consensus CDK phosphorylation site. In some tissular contexts, phosphorylation of Serine180 occurs in asymmetrically dividing cells but not in their symmetrically dividing neighbours. In neuroblasts, Serine180 phosphomutants disrupt the timing of basal polarisation. Serine180 phosphomutants also affect the specification and binary cell fate determination of sensory organ precursors as well as Baz localisation during their asymmetric cell divisions. Finally, we show that CDK1 phosphorylates Serine-S180 and an equivalent Serine on human PAR-3 in vitro.
