Naa12 compensates for Naa10 in mice in the amino-terminal acetylation pathway.

Hyae Yon Kweon,David Bolton,Ahmed Ismail,Shinyeong Ju,Thomas Papazyan,Tae-Young Roh,Andrew Garcia,Leah Gottlieb,Cheolju Lee,Rasmus Ree,Seungwoon Seo,Jonathan Crain,Michael Flory,Elaine Marchi,Mi-Ni Lee,Goo Taeg Oh,Sejin Jeon,Taesoo Kim,Alison Sebold,Ronen Marmorstein,Nina Mctiernan,Thomas Arnesen,Simon J Conway ,Seongkeun Sonn ,Hyun‐Seok Kim ,Scott K Lyons ,Se‐Jin Jeong ,Max J Dörfel ,Gholson J Lyon

doi:10.7554/elife.65952

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.

Highlights

Amino-terminal acetylation is one of the most common protein modifications, occurring co- and post-translationally
To explore the role of Naa10 in development, most analyses were carried out using our Naa10 KO model mice that had been generated previously (Yoon et al, 2014) using a targeting vector deleting Exon1, including the start codon, and Exon2 to Exon4 containing the GNAT domain including the acetyl-CoA binding motif, which is crucial for Naa10 function
Both Naa10-/Y and Naa10tm1a/Y mice were under-represented after birth, while there was no significant reduction in the embryonic stage in both mouse lines (Supplementary file 1a, b)

Summary

Introduction

Amino-terminal acetylation is one of the most common protein modifications, occurring co- and post-translationally. To elucidate the functional role of Naa during development in mice, we used two different Naa10-deficient mouse lines: one, referred to as Naa knockout (KO), which was previously reported related to bone density in postnatal day 3 (P3) mice (Yoon et al, 2014), and another denoted as Naa10tm1a(EUCOMM)Hmgu (Naa10tm1a), generated in this study. We demonstrate that Naa is essential for proper development and Naa, a newly identified paralog of Naa, can play a compensatory role in mice

Results

A Naa10 paralog exists in mice

Discussion

Materials and methods