OLA1 regulates protein synthesis and integrated stress response by inhibiting eIF2 ternary complex formation.
Translation is a fundamental cellular process, and its dysregulation can contribute to human diseases such as cancer. During translation initiation the eukaryotic initiation factor 2 (eIF2) forms a ternary complex (TC) with GTP and the initiator methionyl-tRNA (tRNAi), mediating ribosomal recruitment of tRNAi. Limiting TC availability is a central mechanism for triggering the integrated stress response (ISR), which suppresses global translation in response to various cellular stresses, but induces specific proteins such as ATF4. This study shows that OLA1, a member of the ancient Obg family of GTPases, is an eIF2-regulatory protein that inhibits protein synthesis and promotes ISR by binding eIF2, hydrolyzing GTP, and interfering with TC formation. OLA1 thus represents a novel mechanism of translational control affecting de novo TC formation, different from the traditional model in which phosphorylation of eIF2α blocks the regeneration of TC. Depletion of OLA1 caused a hypoactive ISR and greater survival in stressed cells. In vivo, OLA1-knockdown rendered cancer cells deficient in ISR and the downstream proapoptotic effector, CHOP, promoting tumor growth and metastasis. Our work suggests that OLA1 is a novel translational GTPase and plays a suppressive role in translation and cell survival, as well as cancer growth and progression.
1] Department of Translational Imaging Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA [2] Cancer Institute, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China.
Huarong
H
Chen
Department of Translational Imaging Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA.
Renduo
R
Song
Department of Translational Imaging Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA.
Guohui
G
Wang
Department of Translational Imaging Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA.
Zonghui
Z
Ding
Department of Radiation Oncology Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA.
Chunying
C
Yang
Cancer Institute, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China.
Jiawei
J
Zhang
Department of Pathology and Genomic Medicine Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA.
Zihua
Z
Zeng
Department of Translational Imaging Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA.
Valentina
V
Rubio
Department of Translational Imaging Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA.
Luchang
L
Wang
Department of Translational Imaging Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA.
Nancy
N
Zu
Department of Translational Imaging Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA.
Amanda M
AM
Weiskoff
Immunobiology Research Center Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA.
Laurie J
LJ
Minze
Department of Translational Imaging Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA.
Prince V S
PV
Jeyabal
Department of Translational Imaging Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA.
Oula C
OC
Mansour
Department of Translational Imaging Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA.
Li
L
Bai
Biochemstry Department, Case Western Reserve University, Cleveland, OH 44106, USA.
William C
WC
Merrick
Cancer Institute, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China.
Shu
S
Zheng
Department of Translational Imaging Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA.
Zheng-Zheng
ZZ
Shi
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D018384:Oxidative Stress / Q000502:physiology*; D014176:Protein Biosynthesis / Q000502:physiology*
D015852:Eukaryotic Initiation Factor-2; D000251:Adenosine Triphosphatases; D019204:GTP-Binding Proteins; C522732:OLA1 protein, human