The widely used non-steroidal anti-inflammatory drugs (NSAIDs) are derivatives of the phytohormone salicylic acid (SA). SA is well known to regulate plant immunity and development, whereas there have been few reports focusing on the effects of NSAIDs in plants. Our studies here reveal that NSAIDs exhibit largely overlapping physiological activities to SA in the model plant Arabidopsis. NSAID treatments lead to shorter and agravitropic primary roots and inhibited lateral root organogenesis. Notably, in addition to the SA-like action, which in roots involves binding to the protein phosphatase 2A (PP2A), NSAIDs also exhibit PP2A-independent effects. Cell biological and biochemical analyses reveal that many NSAIDs bind directly to and inhibit the chaperone activity of TWISTED DWARF1, thereby regulating actin cytoskeleton dynamics and subsequent endosomal trafficking. Our findings uncover an unexpected bioactivity of human pharmaceuticals in plants and provide insights into the molecular mechanism underlying the cellular action of this class of anti-inflammatory compounds.

• Klíčová slova
• Arabidopsis, FKBP, NSAID, TWD1, actin filament, auxin, auxin transport inhibitor, endosomal trafficking, non-steroidal anti-inflammatory drug, polar auxin transport,
• MeSH
• aktiny metabolismus   MeSH
• antiflogistika nesteroidní farmakologie   terapeutické užití   MeSH
• Arabidopsis MeSH
• kyseliny indoloctové metabolismus   MeSH
• proteiny huseníčku metabolismus   MeSH
• proteiny vázající takrolimus metabolismus   MeSH
• vývoj rostlin MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aktiny MeSH
• antiflogistika nesteroidní MeSH
• kyseliny indoloctové MeSH
• proteiny huseníčku MeSH
• proteiny vázající takrolimus MeSH
• TWD1 protein, Arabidopsis MeSH Prohlížeč

Auxin phytohormones control most aspects of plant development through a complex and interconnected signaling network. In the presence of auxin, AUXIN/INDOLE-3-ACETIC ACID (AUX/IAA) transcriptional repressors are targeted for degradation by the SKP1-CULLIN1-F-BOX (SCF) ubiquitin-protein ligases containing TRANSPORT INHIBITOR RESISTANT 1/AUXIN SIGNALING F-BOX (TIR1/AFB). CULLIN1-neddylation is required for SCFTIR1/AFB functionality, as exemplified by mutants deficient in the NEDD8-activating enzyme subunit AUXIN-RESISTANT 1 (AXR1). Here, we report a chemical biology screen that identifies small molecules requiring AXR1 to modulate plant development. We selected four molecules of interest, RubNeddin 1 to 4 (RN1 to -4), among which RN3 and RN4 trigger selective auxin responses at transcriptional, biochemical, and morphological levels. This selective activity is explained by their ability to consistently promote the interaction between TIR1 and a specific subset of AUX/IAA proteins, stimulating the degradation of particular AUX/IAA combinations. Finally, we performed a genetic screen using RN4, the RN with the greatest potential for dissecting auxin perception, which revealed that the chromatin remodeling ATPase BRAHMA is implicated in auxin-mediated apical hook development. These results demonstrate the power of selective auxin agonists to dissect auxin perception for plant developmental functions, as well as offering opportunities to discover new molecular players involved in auxin responses.

• Klíčová slova
• auxin, chemical biology, hormone perception, prohormone, selective agonist,
• MeSH
• Arabidopsis genetika   metabolismus   MeSH
• F-box proteiny metabolismus   MeSH
• genetická transkripce účinky léků   MeSH
• geneticky modifikované rostliny genetika   MeSH
• kyseliny indoloctové metabolismus   MeSH
• protein NEDD8 genetika   MeSH
• proteinligasy komplexu SCF metabolismus   MeSH
• proteiny huseníčku genetika   metabolismus   MeSH
• proteolýza * MeSH
• receptory buněčného povrchu metabolismus   MeSH
• regulace genové exprese u rostlin MeSH
• regulátory růstu rostlin genetika   metabolismus   MeSH
• semenáček metabolismus   MeSH
• signální transdukce MeSH
• transkripční faktory metabolismus   MeSH
• vývoj rostlin genetika   fyziologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• F-box proteiny MeSH
• indoleacetic acid MeSH Prohlížeč
• kyseliny indoloctové MeSH
• protein NEDD8 MeSH
• proteinligasy komplexu SCF MeSH
• proteiny huseníčku MeSH
• receptory buněčného povrchu MeSH
• regulátory růstu rostlin MeSH
• transkripční faktory MeSH

Plant growth and architecture is regulated by the polar distribution of the hormone auxin. Polarity and flexibility of this process is provided by constant cycling of auxin transporter vesicles along actin filaments, coordinated by a positive auxin-actin feedback loop. Both polar auxin transport and vesicle cycling are inhibited by synthetic auxin transport inhibitors, such as 1-N-naphthylphthalamic acid (NPA), counteracting the effect of auxin; however, underlying targets and mechanisms are unclear. Using NMR, we map the NPA binding surface on the Arabidopsis thaliana ABCB chaperone TWISTED DWARF1 (TWD1). We identify ACTIN7 as a relevant, although likely indirect, TWD1 interactor, and show TWD1-dependent regulation of actin filament organization and dynamics and that TWD1 is required for NPA-mediated actin cytoskeleton remodeling. The TWD1-ACTIN7 axis controls plasma membrane presence of efflux transporters, and as a consequence act7 and twd1 share developmental and physiological phenotypes indicative of defects in auxin transport. These can be phenocopied by NPA treatment or by chemical actin (de)stabilization. We provide evidence that TWD1 determines downstream locations of auxin efflux transporters by adjusting actin filament debundling and dynamizing processes and mediating NPA action on the latter. This function appears to be evolutionary conserved since TWD1 expression in budding yeast alters actin polarization and cell polarity and provides NPA sensitivity.

• MeSH
• Arabidopsis genetika   metabolismus   MeSH
• biologický transport genetika   fyziologie   MeSH
• kyseliny indoloctové metabolismus   MeSH
• mikrofilamenta metabolismus   MeSH
• proteiny huseníčku genetika   metabolismus   MeSH
• proteiny vázající takrolimus genetika   metabolismus   MeSH
• regulace genové exprese u rostlin genetika   fyziologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kyseliny indoloctové MeSH
• proteiny huseníčku MeSH
• proteiny vázající takrolimus MeSH
• TWD1 protein, Arabidopsis MeSH Prohlížeč