TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BP and TIA-1.
TAR deoxyribonucleic acid-binding protein 43 (TDP-43) is a multifunctional protein with roles in transcription, pre-messenger ribonucleic acid (mRNA) splicing, mRNA stability and transport. TDP-43 interacts with other heterogeneous nuclear ribonucleoproteins (hnRNPs), including hnRNP A2, via its C-terminus and several hnRNP family members are involved in the cellular stress response. This relationship led us to investigate the role of TDP-43 in cellular stress. Our results demonstrate that TDP-43 and hnRNP A2 are localized to stress granules (SGs), following oxidative stress, heat shock and exposure to thapsigargin. TDP-43 contributes to both the assembly and maintenance of SGs in response to oxidative stress and differentially regulates key SGs components, including TIA-1 and G3BP. The controlled aggregation of TIA-1 is disrupted in the absence of TDP-43 resulting in slowed SG formation. In addition, TDP-43 regulates the levels of G3BP mRNA, a SG nucleating factor. The disease-associated mutation TDP-43(R361S) is a loss-of-function mutation with regards to SG formation and confers alterations in levels of G3BP and TIA-1. In contrast, a second mutation TDP-43(D169G) does not impact this pathway. Thus, mutations in TDP-43 are mechanistically divergent. Finally, the cellular function of TDP-43 extends beyond splicing and places TDP-43 as a participant of the central cellular response to stress and an active player in RNA storage.
Centre d'excellence en neuromique de l'Université de Montréal, Centre de recherche du CHUM, Montréal, QC, Canada.
Karli K
KK
McDonald
Anaïs
A
Aulas
Laurie
L
Destroismaisons
Sarah
S
Pickles
Evghenia
E
Beleac
William
W
Camu
Guy A
GA
Rouleau
Christine
C
Vande Velde
D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003594:Cytoplasmic Granules / Q000235:genetics / Q000378:metabolism*; D004265:DNA Helicases; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D018384:Oxidative Stress / Q000502:physiology*; D039102:Poly(A)-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D020365:RNA Helicases; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism*; D000067776:RNA Recognition Motif Proteins; D012326:RNA Splicing / Q000502:physiology*; D020871:RNA Stability / Q000502:physiology*; D000074019:T-Cell Intracellular Antigen-1
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D039102:Poly(A)-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D012322:RNA Precursors; D000067776:RNA Recognition Motif Proteins; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human; C439768:hnRNP A2; D004265:DNA Helicases; C116070:G3BP1 protein, human; D020365:RNA Helicases