METTL14-mediated m6A methylation orchestrates early NK cell development by maintaining metabolic fitness
- 1Hefei, China
Abstract
N6-methyladenosine (m6A) represents the most abundant mRNA modification, yet its role in natural killer (NK) cell development remains incompletely understood. Here we demonstrate that the m6A methyltransferase METTL14 plays an indispensable, stage-specific role in early NK cell development. Mettl14 deficiency at the progenitor stage caused severe NK cell lymphopenia by disrupting the NK progenitor to immature NK cell transition. Paradoxically, residual Mettl14-null NK cells exhibited a hypermetabolic state characterized by mTORC1 hyperactivation and enhanced mitochondrial function, which drove both hyperproliferation and activation-induced cell death via p53 and apoptotic pathway activation. Despite developmental defects, these cells demonstrated superior capacity to control melanoma metastasis in vivo. Mechanistically, METTL14 fine-tuned IL-15 responsiveness likely by sustaining SOCS3 expression to restrain JAK-STAT5 signaling. Terminal deletion of Mettl14 produced no phenotype, underscoring its specific requirement during early development. Our findings establish METTL14 as a crucial checkpoint coordinating transcriptional and metabolic programs to ensure NK cell homeostasis.
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BibTeX
@article{ma2026mettl14mediated,
title = {{METTL14-mediated m6A methylation orchestrates early NK cell development by maintaining metabolic fitness}},
author = {Huan Ma and Zhenzhen Tu and Surong Deng and Yirong Sun and Shuxin Wang and Hongxia Wang and Chen Cheng and Xiang Li and Zhongjun Dong and Shasha Chen},
journal = {Cell death \& disease},
year = {2026},
month = jul,
doi = {10.1038/s41419-026-09069-2},
url = {https://europepmc.org/article/PMC/PMC13690738},
note = {CC BY},
}
RIS
TY - JOUR
TI - METTL14-mediated m6A methylation orchestrates early NK cell development by maintaining metabolic fitness
AU - Huan Ma
AU - Zhenzhen Tu
AU - Surong Deng
AU - Yirong Sun
AU - Shuxin Wang
AU - Hongxia Wang
AU - Chen Cheng
AU - Xiang Li
AU - Zhongjun Dong
AU - Shasha Chen
PY - 2026
DA - 2026/07/01
JO - Cell death & disease
DO - 10.1038/s41419-026-09069-2
UR - https://europepmc.org/article/PMC/PMC13690738
AB - N6-methyladenosine (m6A) represents the most abundant mRNA modification, yet its role in natural killer (NK) cell development remains incompletely understood. Here we demonstrate that the m6A methyltransferase METTL14 plays an indispensable, stage-specific role in early NK cell development. Mettl14 deficiency at the progenitor stage caused severe NK cell lymphopenia by disrupting the NK progenitor to immature NK cell transition. Paradoxically, residual Mettl14-null NK cells exhibited a hypermetabolic state characterized by mTORC1 hyperactivation and enhanced mitochondrial function, which drove both hyperproliferation and activation-induced cell death via p53 and apoptotic pathway activation. Despite developmental defects, these cells demonstrated superior capacity to control melanoma metastasis in vivo. Mechanistically, METTL14 fine-tuned IL-15 responsiveness likely by sustaining SOCS3 expression to restrain JAK-STAT5 signaling. Terminal deletion of Mettl14 produced no phenotype, underscoring its specific requirement during early development. Our findings establish METTL14 as a crucial checkpoint coordinating transcriptional and metabolic programs to ensure NK cell homeostasis.
SN - 2041-4889
ER -