PMID- 23976881
OWN - NLM
STAT- MEDLINE
DCOM- 20140306
LR  - 20220321
IS  - 1545-7885 (Electronic)
IS  - 1544-9173 (Print)
IS  - 1544-9173 (Linking)
VI  - 11
IP  - 8
DP  - 2013
TI  - The HILDA complex coordinates a conditional switch in the 3'-untranslated region 
      of the VEGFA mRNA.
PG  - e1001635
LID - 10.1371/journal.pbio.1001635 [doi]
LID - e1001635
AB  - Cell regulatory circuits integrate diverse, and sometimes conflicting, 
      environmental cues to generate appropriate, condition-dependent responses. Here, 
      we elucidate the components and mechanisms driving a protein-directed RNA switch 
      in the 3'UTR of vascular endothelial growth factor (VEGF)-A. We describe a novel 
      HILDA (hypoxia-inducible hnRNP L-DRBP76-hnRNP A2/B1) complex that coordinates a 
      three-element RNA switch, enabling VEGFA mRNA translation during combined hypoxia 
      and inflammation. In addition to binding the CA-rich element (CARE), 
      heterogeneous nuclear ribonucleoprotein (hnRNP) L regulates switch assembly and 
      function. hnRNP L undergoes two previously unrecognized, condition-dependent 
      posttranslational modifications: IFN-gamma induces prolyl hydroxylation and von 
      Hippel-Lindau (VHL)-mediated proteasomal degradation, whereas hypoxia stimulates 
      hnRNP L phosphorylation at Tyr(359), inducing binding to hnRNP A2/B1, which 
      stabilizes the protein. Also, phospho-hnRNP L recruits DRBP76 (double-stranded 
      RNA binding protein 76) to the 3'UTR, where it binds an adjacent AU-rich 
      stem-loop (AUSL) element, "flipping" the RNA switch by disrupting the GAIT 
      (interferon-gamma-activated inhibitor of translation) element, preventing GAIT 
      complex binding, and driving robust VEGFA mRNA translation. The signal-dependent, 
      HILDA complex coordinates the function of a trio of neighboring RNA elements, 
      thereby regulating translation of VEGFA and potentially other mRNA targets. The 
      VEGFA RNA switch might function to ensure appropriate angiogenesis and tissue 
      oxygenation during conflicting signals from combined inflammation and hypoxia. We 
      propose the VEGFA RNA switch as an archetype for signal-activated, 
      protein-directed, multi-element RNA switches that regulate posttranscriptional 
      gene expression in complex environments.
FAU - Yao, Peng
AU  - Yao P
AD  - Department of Cellular and Molecular Medicine, Lerner Research Institute, 
      Cleveland Clinic, Cleveland, Ohio, USA.
FAU - Potdar, Alka A
AU  - Potdar AA
FAU - Ray, Partho Sarothi
AU  - Ray PS
FAU - Eswarappa, Sandeepa M
AU  - Eswarappa SM
FAU - Flagg, Andrew C
AU  - Flagg AC
FAU - Willard, Belinda
AU  - Willard B
FAU - Fox, Paul L
AU  - Fox PL
LA  - eng
GR  - R01 GM086430/GM/NIGMS NIH HHS/United States
GR  - P01 HL076491/HL/NHLBI NIH HHS/United States
GR  - P01 HL029582/HL/NHLBI NIH HHS/United States
GR  - R01 DK083359/DK/NIDDK NIH HHS/United States
GR  - UL1 TR000439/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130820
PL  - United States
TA  - PLoS Biol
JT  - PLoS biology
JID - 101183755
RN  - 0 (3' Untranslated Regions)
RN  - 0 (Heterogeneous-Nuclear Ribonucleoprotein Group A-B)
RN  - 0 (Heterogeneous-Nuclear Ribonucleoprotein L)
RN  - 0 (ILF3 protein, human)
RN  - 0 (Nuclear Factor 90 Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (hnRNP A2)
SB  - IM
MH  - 3' Untranslated Regions/*genetics
MH  - Cell Line
MH  - Fluorescent Antibody Technique
MH  - Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics/*metabolism
MH  - Heterogeneous-Nuclear Ribonucleoprotein L/genetics/*metabolism
MH  - Humans
MH  - Mass Spectrometry
MH  - Mutagenesis, Site-Directed
MH  - Nuclear Factor 90 Proteins/genetics/*metabolism
MH  - RNA, Messenger/*genetics
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Ubiquitination/genetics/physiology
MH  - Vascular Endothelial Growth Factor A/*genetics
PMC - PMC3747992
COIS- The authors have declared that no competing interests exist.
EDAT- 2013/08/27 06:00
MHDA- 2014/03/07 06:00
PMCR- 2013/08/20
CRDT- 2013/08/27 06:00
PHST- 2013/01/14 00:00 [received]
PHST- 2013/07/12 00:00 [accepted]
PHST- 2013/08/27 06:00 [entrez]
PHST- 2013/08/27 06:00 [pubmed]
PHST- 2014/03/07 06:00 [medline]
PHST- 2013/08/20 00:00 [pmc-release]
AID - PBIOLOGY-D-13-00165 [pii]
AID - 10.1371/journal.pbio.1001635 [doi]
PST - ppublish
SO  - PLoS Biol. 2013;11(8):e1001635. doi: 10.1371/journal.pbio.1001635. Epub 2013 Aug 
      20.