TY - JOUR
T1 - eIF3 mRNA selectivity profiling reveals eIF3k as a cancer-relevant regulator of ribosome content
AU - Duan, Haoran
AU - Zhang, Siqiong
AU - Zarai, Yoram
AU - Öllinger, Rupert
AU - Wu, Yanmeng
AU - Sun, Li
AU - Hu, Cheng
AU - He, Yaohui
AU - Tian, Guiyou
AU - Rad, Roland
AU - Kong, Xiangquan
AU - Cheng, Yabin
AU - Tuller, Tamir
AU - Wolf, Dieter A.
N1 - Publisher Copyright:
© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
PY - 2023/6/15
Y1 - 2023/6/15
N2 - eIF3, whose subunits are frequently overexpressed in cancer, regulates mRNA translation from initiation to termination, but mRNA-selective functions of individual subunits remain poorly defined. Using multiomic profiling upon acute depletion of eIF3 subunits, we observed that while eIF3a, b, e, and f markedly differed in their impact on eIF3 holo-complex formation and translation, they were each required for cancer cell proliferation and tumor growth. Remarkably, eIF3k showed the opposite pattern with depletion promoting global translation, cell proliferation, tumor growth, and stress resistance through repressing the synthesis of ribosomal proteins, especially RPS15A. Whereas ectopic expression of RPS15A mimicked the anabolic effects of eIF3k depletion, disruption of eIF3 binding to the 5′-UTR of RSP15A mRNA negated them. eIF3k and eIF3l are selectively downregulated in response to endoplasmic reticulum and oxidative stress. Supported by mathematical modeling, our data uncover eIF3k-l as a mRNA-specific module which, through controlling RPS15A translation, serves as a rheostat of ribosome content, possibly to secure spare translational capacity that can be mobilized during stress.
AB - eIF3, whose subunits are frequently overexpressed in cancer, regulates mRNA translation from initiation to termination, but mRNA-selective functions of individual subunits remain poorly defined. Using multiomic profiling upon acute depletion of eIF3 subunits, we observed that while eIF3a, b, e, and f markedly differed in their impact on eIF3 holo-complex formation and translation, they were each required for cancer cell proliferation and tumor growth. Remarkably, eIF3k showed the opposite pattern with depletion promoting global translation, cell proliferation, tumor growth, and stress resistance through repressing the synthesis of ribosomal proteins, especially RPS15A. Whereas ectopic expression of RPS15A mimicked the anabolic effects of eIF3k depletion, disruption of eIF3 binding to the 5′-UTR of RSP15A mRNA negated them. eIF3k and eIF3l are selectively downregulated in response to endoplasmic reticulum and oxidative stress. Supported by mathematical modeling, our data uncover eIF3k-l as a mRNA-specific module which, through controlling RPS15A translation, serves as a rheostat of ribosome content, possibly to secure spare translational capacity that can be mobilized during stress.
KW - RPS15A
KW - cancer growth control
KW - mRNA selectivity
KW - ribosome content
KW - translation initiation factor 3
UR - http://www.scopus.com/inward/record.url?scp=85158160487&partnerID=8YFLogxK
U2 - 10.15252/embj.2022112362
DO - 10.15252/embj.2022112362
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C2 - 37155573
AN - SCOPUS:85158160487
SN - 0261-4189
VL - 42
JO - EMBO Journal
JF - EMBO Journal
IS - 12
M1 - e112362
ER -
