Transfer RNA acetylation regulates in vivo mammalian stress signaling

Supuni Thalalla Gamage; Roxane Khoogar; Shereen Howpay Manage; Judey T. DaRos; McKenna C. Crawford; Joe Georgeson; Bogdan V. Polevoda; Chelsea Sanders; Kendall A. Lee; Kellie D. Nance; Vinithra Iyer; Anatoly Kustanovich; Minervo Perez; Chu T. Thu; Sam R. Nance; Ruhul Amin; Christine N. Miller; Ronald J. Holewinski; Sudipto Das; Thomas J. Meyer; Vishal Koparde; Acong Yang; Parthav Jailwala; Joe T. Nguyen; Thorkell Andresson; Kent Hunter; Shuo Gu; Beverly A. Mock; Elijah F. Edmondson; Simone Difilippantonio; Raj Chari; Schraga Schwartz; Mitchell R. O’Connell; Colin Chih Chien Wu; Jordan L. Meier

doi:10.1126/sciadv.ads2923

Transfer RNA acetylation regulates in vivo mammalian stress signaling

Supuni Thalalla Gamage, Roxane Khoogar, Shereen Howpay Manage, Judey T. DaRos, McKenna C. Crawford, Joe Georgeson, Bogdan V. Polevoda, Chelsea Sanders, Kendall A. Lee, Kellie D. Nance, Vinithra Iyer, Anatoly Kustanovich, Minervo Perez, Chu T. Thu, Sam R. Nance, Ruhul Amin, Christine N. Miller, Ronald J. Holewinski, Sudipto Das, Thomas J. MeyerVishal Koparde, Acong Yang, Parthav Jailwala, Joe T. Nguyen, Thorkell Andresson, Kent Hunter, Shuo Gu, Beverly A. Mock, Elijah F. Edmondson, Simone Difilippantonio, Raj Chari, Schraga Schwartz, Mitchell R. O’Connell, Colin Chih Chien Wu, Jordan L. Meier

Department of Molecular Genetics

Weizmann Institute of Science

Research output: Contribution to journal › Article › peer-review

Abstract

Transfer RNA (tRNA) modifications are crucial for protein synthesis, but their position-specific physiological roles remain poorly understood. Here, we investigate the impact of N⁴-acetylcytidine (ac⁴C), a highly conserved tRNA modification catalyzed by the essential acetyltransferase Nat10. By targeting Thumpd1, a nonessential adapter protein required for Nat10-catalyzed tRNA acetylation, we determine that loss of tRNA acetylation leads to reduced levels of tRNA^Leu, increased ribosome stalling, and activation of eIF2α phosphorylation. Thumpd1 knockout mice exhibit growth defects and sterility. Concurrent knockout of Thumpd1 and the stress-sensing kinase Gcn2 causes penetrant postnatal lethality in mice, indicating a critical genetic interaction. Our findings demonstrate that a modification restricted to a single position within type II cytosolic tRNAs can regulate ribosome-mediated stress signaling in mammalian organisms, with implications for our understanding of translational control and therapeutic interventions.

Original language	English
Article number	eads2923
Journal	Science Advances
Volume	11
Issue number	12
DOIs	https://doi.org/10.1126/sciadv.ads2923
State	Published - 21 Mar 2025

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Gamage, S. T., Khoogar, R., Manage, S. H., DaRos, J. T., Crawford, M. C., Georgeson, J., Polevoda, B. V., Sanders, C., Lee, K. A., Nance, K. D., Iyer, V., Kustanovich, A., Perez, M., Thu, C. T., Nance, S. R., Amin, R., Miller, C. N., Holewinski, R. J., Das, S., ... Meier, J. L. (2025). Transfer RNA acetylation regulates in vivo mammalian stress signaling. Science Advances, 11(12), Article eads2923. https://doi.org/10.1126/sciadv.ads2923

@article{0be77b1104ac4ec18d0ea6cbb4088d92,

title = "Transfer RNA acetylation regulates in vivo mammalian stress signaling",

abstract = "Transfer RNA (tRNA) modifications are crucial for protein synthesis, but their position-specific physiological roles remain poorly understood. Here, we investigate the impact of N4-acetylcytidine (ac4C), a highly conserved tRNA modification catalyzed by the essential acetyltransferase Nat10. By targeting Thumpd1, a nonessential adapter protein required for Nat10-catalyzed tRNA acetylation, we determine that loss of tRNA acetylation leads to reduced levels of tRNALeu, increased ribosome stalling, and activation of eIF2α phosphorylation. Thumpd1 knockout mice exhibit growth defects and sterility. Concurrent knockout of Thumpd1 and the stress-sensing kinase Gcn2 causes penetrant postnatal lethality in mice, indicating a critical genetic interaction. Our findings demonstrate that a modification restricted to a single position within type II cytosolic tRNAs can regulate ribosome-mediated stress signaling in mammalian organisms, with implications for our understanding of translational control and therapeutic interventions.",

author = "Gamage, {Supuni Thalalla} and Roxane Khoogar and Manage, {Shereen Howpay} and DaRos, {Judey T.} and Crawford, {McKenna C.} and Joe Georgeson and Polevoda, {Bogdan V.} and Chelsea Sanders and Lee, {Kendall A.} and Nance, {Kellie D.} and Vinithra Iyer and Anatoly Kustanovich and Minervo Perez and Thu, {Chu T.} and Nance, {Sam R.} and Ruhul Amin and Miller, {Christine N.} and Holewinski, {Ronald J.} and Sudipto Das and Meyer, {Thomas J.} and Vishal Koparde and Acong Yang and Parthav Jailwala and Nguyen, {Joe T.} and Thorkell Andresson and Kent Hunter and Shuo Gu and Mock, {Beverly A.} and Edmondson, {Elijah F.} and Simone Difilippantonio and Raj Chari and Schraga Schwartz and O{\textquoteright}Connell, {Mitchell R.} and Wu, {Colin Chih Chien} and Meier, {Jordan L.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2025 The Authors, some rights reserved.",

year = "2025",

month = mar,

day = "21",

doi = "10.1126/sciadv.ads2923",

language = "الإنجليزيّة",

volume = "11",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "12",

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Gamage, ST, Khoogar, R, Manage, SH, DaRos, JT, Crawford, MC, Georgeson, J, Polevoda, BV, Sanders, C, Lee, KA, Nance, KD, Iyer, V, Kustanovich, A, Perez, M, Thu, CT, Nance, SR, Amin, R, Miller, CN, Holewinski, RJ, Das, S, Meyer, TJ, Koparde, V, Yang, A, Jailwala, P, Nguyen, JT, Andresson, T, Hunter, K, Gu, S, Mock, BA, Edmondson, EF, Difilippantonio, S, Chari, R, Schwartz, S, O’Connell, MR, Wu, CCC & Meier, JL 2025, 'Transfer RNA acetylation regulates in vivo mammalian stress signaling', Science Advances, vol. 11, no. 12, eads2923. https://doi.org/10.1126/sciadv.ads2923

TY - JOUR

T1 - Transfer RNA acetylation regulates in vivo mammalian stress signaling

AU - Gamage, Supuni Thalalla

AU - Khoogar, Roxane

AU - Manage, Shereen Howpay

AU - DaRos, Judey T.

AU - Crawford, McKenna C.

AU - Georgeson, Joe

AU - Polevoda, Bogdan V.

AU - Sanders, Chelsea

AU - Lee, Kendall A.

AU - Nance, Kellie D.

AU - Iyer, Vinithra

AU - Kustanovich, Anatoly

AU - Perez, Minervo

AU - Thu, Chu T.

AU - Nance, Sam R.

AU - Amin, Ruhul

AU - Miller, Christine N.

AU - Holewinski, Ronald J.

AU - Das, Sudipto

AU - Meyer, Thomas J.

AU - Koparde, Vishal

AU - Yang, Acong

AU - Jailwala, Parthav

AU - Nguyen, Joe T.

AU - Andresson, Thorkell

AU - Hunter, Kent

AU - Gu, Shuo

AU - Mock, Beverly A.

AU - Edmondson, Elijah F.

AU - Difilippantonio, Simone

AU - Chari, Raj

AU - Schwartz, Schraga

AU - O’Connell, Mitchell R.

AU - Wu, Colin Chih Chien

AU - Meier, Jordan L.

PY - 2025/3/21

Y1 - 2025/3/21

N2 - Transfer RNA (tRNA) modifications are crucial for protein synthesis, but their position-specific physiological roles remain poorly understood. Here, we investigate the impact of N4-acetylcytidine (ac4C), a highly conserved tRNA modification catalyzed by the essential acetyltransferase Nat10. By targeting Thumpd1, a nonessential adapter protein required for Nat10-catalyzed tRNA acetylation, we determine that loss of tRNA acetylation leads to reduced levels of tRNALeu, increased ribosome stalling, and activation of eIF2α phosphorylation. Thumpd1 knockout mice exhibit growth defects and sterility. Concurrent knockout of Thumpd1 and the stress-sensing kinase Gcn2 causes penetrant postnatal lethality in mice, indicating a critical genetic interaction. Our findings demonstrate that a modification restricted to a single position within type II cytosolic tRNAs can regulate ribosome-mediated stress signaling in mammalian organisms, with implications for our understanding of translational control and therapeutic interventions.

AB - Transfer RNA (tRNA) modifications are crucial for protein synthesis, but their position-specific physiological roles remain poorly understood. Here, we investigate the impact of N4-acetylcytidine (ac4C), a highly conserved tRNA modification catalyzed by the essential acetyltransferase Nat10. By targeting Thumpd1, a nonessential adapter protein required for Nat10-catalyzed tRNA acetylation, we determine that loss of tRNA acetylation leads to reduced levels of tRNALeu, increased ribosome stalling, and activation of eIF2α phosphorylation. Thumpd1 knockout mice exhibit growth defects and sterility. Concurrent knockout of Thumpd1 and the stress-sensing kinase Gcn2 causes penetrant postnatal lethality in mice, indicating a critical genetic interaction. Our findings demonstrate that a modification restricted to a single position within type II cytosolic tRNAs can regulate ribosome-mediated stress signaling in mammalian organisms, with implications for our understanding of translational control and therapeutic interventions.

UR - http://www.scopus.com/inward/record.url?scp=105000880522&partnerID=8YFLogxK

U2 - 10.1126/sciadv.ads2923

DO - 10.1126/sciadv.ads2923

M3 - مقالة

SN - 2375-2548

VL - 11

JO - Science Advances

JF - Science Advances

IS - 12

M1 - eads2923

ER -

Transfer RNA acetylation regulates in vivo mammalian stress signaling

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