Naa12 compensates for Naa10 in mice in the amino-terminal acetylation pathway
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Curated by eLife
Evaluation Summary:
This manuscript describes the identification of an animal model that reproduces several features presented in Ogden syndrome patients and reveals the roles of two N-terminal acetyltransferases in mouse development. It will be of interest to the readers in the field of protein acetylation and modification, and also to the scientific community involved in rare diseases and syndrome studies.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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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 paralog 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.
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Reviewer #3 (Public Review):
Mutations in Naa10 are known to be causative in Ogden syndrome, a genetic disorder associated with infantile death. The paper by Kweon et al describes a series of experiments using mouse models of Naa10, an x-linked gene with the function of a major acetyltranferase in a complex accounting for 40-50% of acetylation of all proteins. The lack of complete embryonic lethality in the Naa10 hemizygous mice, leads the authors discover a paralogous mouse gene Naa12. The authors further demonstrate that Naa12 can compensate for Naa10 loss of function and that null mutations in both genes lead to complete embryonic lethality.
Genetic experiments described in this paper involve 2 distinct knockouts of the Naa10 in mice. The resulting hemizygous male mice displayed a variety of developmental defects, and while …
Reviewer #3 (Public Review):
Mutations in Naa10 are known to be causative in Ogden syndrome, a genetic disorder associated with infantile death. The paper by Kweon et al describes a series of experiments using mouse models of Naa10, an x-linked gene with the function of a major acetyltranferase in a complex accounting for 40-50% of acetylation of all proteins. The lack of complete embryonic lethality in the Naa10 hemizygous mice, leads the authors discover a paralogous mouse gene Naa12. The authors further demonstrate that Naa12 can compensate for Naa10 loss of function and that null mutations in both genes lead to complete embryonic lethality.
Genetic experiments described in this paper involve 2 distinct knockouts of the Naa10 in mice. The resulting hemizygous male mice displayed a variety of developmental defects, and while hemizygous males were underrepresented at birth, some surviving mice experienced early neonatal lethality while a proportion of the hemizygous mice survived to adulthood. Severely affected animals exhibited a variety of development abnormalities but importantly, no major reductions in the acetylation patterns were observed. A similar spectrum of phenotypes were reported in 2017 in a separate paper by Lee et al. The lack of complete embryonic lethality in Naa10 hemizygous males led to the hypothesis that a compensatory gene in mice may exist. The authors then identified the autosomal Naa12 gene in mice. This is a major finding of the paper. Naa12 and Naa10 share 80% sequence identity. The authors continued on to generate a Naa12 knockout mouse that in combination with the Naa10 knockout mice, demonstrate complete embryonic lethality to support the hypothesis that Naa12 is a function homolog to Naa10 in mice. This is strong evidence supporting the functional compensation of Naa12. The authors provided a thorough account of the variety of development abnormalities in the Naa10 hemizygous mice at all stages of development, noting changes in bodyweight, hydrocephaly and significant cardiac defects, pigmentation, skeletal and reproductive abnormalities. The variation and heterogeneity ranged from severe embryonic abnormalities through to milder phenotypes in surviving adults. Importantly, the authors identified several phenotypes in the mice that upon further analysis, we also not in the patients with an assumption of incomplete penetrance.
This reviewer finds this paper to be an important finding worthy of publication. The experiments were well powered and the genetic crosses thoroughly examined. The discussion was thoughtful and considered mechanisms of compensation between Naa10 and Naa12 based on the observed experiments.
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Reviewer #2 (Public Review):
This manuscript shows the functional relevance of mNatA catalytic subunit, mNAA10, in mammals' development. Moreover, authors have found a new NatA catalytic subunit in mice, mNAA12, that can compensate mNAA10 inactivation in mice. Interestingly, inactivation of mNAA10 in mice induces some developmental defects similar to those observed in Ogden syndrome (OS) patients including lethality in infants. This study provides several evidences and explains some of the defects observed in OS patients like supernumerary vertebrae and hydrocephaly supporting the relevance of hNAA10 mutations in the development of OS. Moreover, authors have observed in mice some developmental deficiencies not observed previously in OS patients, like supernumerary ribs, that after patient re-examination they have been observed in humans …
Reviewer #2 (Public Review):
This manuscript shows the functional relevance of mNatA catalytic subunit, mNAA10, in mammals' development. Moreover, authors have found a new NatA catalytic subunit in mice, mNAA12, that can compensate mNAA10 inactivation in mice. Interestingly, inactivation of mNAA10 in mice induces some developmental defects similar to those observed in Ogden syndrome (OS) patients including lethality in infants. This study provides several evidences and explains some of the defects observed in OS patients like supernumerary vertebrae and hydrocephaly supporting the relevance of hNAA10 mutations in the development of OS. Moreover, authors have observed in mice some developmental deficiencies not observed previously in OS patients, like supernumerary ribs, that after patient re-examination they have been observed in humans too. Curiously, the results presented in this article show that inactivation of mNatA catalytic subunit does not affects dramatically protein N-terminal acetylation, probably as consequence of mNAA12 paralog function as mNatA catalytic subunit when mNAA10 is not present. Interestingly, gene inactivation supports the biological significance of NAA10 as the main NatA catalytic subunit as mNAA12 inactivation is not associated with any clear phenotype. In spite of being one of the most frequent protein modifications protein N-terminal acetylation has not attracted proper attention, therefore this paper can draw more attention to this important protein modification.
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Reviewer #1 (Public Review):
In this paper, the authors investigated the role of the N-terminal acetyltransferase Naa10 in mouse development. In addition, they identified a new paralog, Naa12, and demonstrated that it has a redundant role with Naa10 in controlling mouse embryonic development. The results are very clear and should be of interests to those working on development and N-terminal acetylation.
I have several comments for the authors to consider:
It is important to show that N-terminal acetylation is lost in the double knockouts. Only with that, the authors can conclude that they have identified the "the complete machinery for the process of amino-terminal acetylation of proteins in mouse development."
Naa12 is new, so if not done yet, the sequence needs to be deposited into Genbank.
The presentation needs to be polished.
i) The …
Reviewer #1 (Public Review):
In this paper, the authors investigated the role of the N-terminal acetyltransferase Naa10 in mouse development. In addition, they identified a new paralog, Naa12, and demonstrated that it has a redundant role with Naa10 in controlling mouse embryonic development. The results are very clear and should be of interests to those working on development and N-terminal acetylation.
I have several comments for the authors to consider:
It is important to show that N-terminal acetylation is lost in the double knockouts. Only with that, the authors can conclude that they have identified the "the complete machinery for the process of amino-terminal acetylation of proteins in mouse development."
Naa12 is new, so if not done yet, the sequence needs to be deposited into Genbank.
The presentation needs to be polished.
i) The title "Naa12 rescues embryonic lethality in Naa10-Deficient 1 Mice in the amino-terminal acetylation pathway" is misleading. When I saw the title, I got the impression that Naa10-dficient 1 mice show embryonic lethality. I would suggest to change it to indicate that Naa10 and Naa12 have redundant roles in embryonic development. Also, "Naa10-Deficient 1 Mice" needs to be changed to "Naa10-deficient mice."
ii) In the impact statement "Mice doubly deficient for Naa10 and Naa12 display embryonic lethality...", the word "doubly " is unnecessary.
iii) Too many acronyms, which make the reading a bit difficult. The terms NTA and Nt-acetylation could be avoided. iv) At the end of page 9, please cite the sequence alignment in Fig. S6
v) On page 12, "Naa12 may rescue loss of Naa10 in mice" could be more assertive.
vi) Overall, I feel that the authors could polish the manuscript so that the salient points could be conveyed more easily to readers.
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Evaluation Summary:
This manuscript describes the identification of an animal model that reproduces several features presented in Ogden syndrome patients and reveals the roles of two N-terminal acetyltransferases in mouse development. It will be of interest to the readers in the field of protein acetylation and modification, and also to the scientific community involved in rare diseases and syndrome studies.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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