Biology subjects

Shields, A.

Publications and source records attributed to Shields, A..

4 recordsLinked to original sources

bioRxiv2023

Warm temperature suppresses plant systemic acquired resistance by intercepting the N-hydroxypipecolic acid immune pathway

Climate warming influences disease development by targeting critical components of the plant immune system, including pattern-triggered immunity (PTI), effector-triggered immunity (ETI) and production of the central defence hormone salicylic acid (SA) at the primary pathogen infection site. However, it is not clear if and/or how temperature impacts systemic immunity. Here we show that pathogen-triggered systemic acquired resistance (SAR) in Arabidopsis thaliana is suppressed at elevated temperature. This was accompanied by global downregulation of SAR-induced genes at elevated temperature. Abolished SAR under warmer conditions was associated with reduced biosynthesis of the SAR metabolite N-hydroxypipecolic acid (NHP) in Arabidopsis and other plant species (such as tomato and rapeseed), as demonstrated by downregulation of NHP biosynthetic genes (ALD1 and FMO1) and reduced NHP and pipecolic acid (Pip) levels. Although multiple SAR signals have been shown previously, exogenous NHP or Pip was sufficient to restore disease protection at elevated temperature, indicating that heat-mediated SAR suppression is due to downregulation of the NHP pathway. Along with ALD1 and FMO1, local and systemic expression of the SA biosynthetic gene ICS1 were also suppressed at warm temperature. Finally, we define a transcriptional network controlling thermosensitive NHP pathway via the master transcription factors CBP60g and SARD1. Our findings demonstrate that warm temperatures impact not only local but also systemic immunity by impinging on NHP biosynthesis, providing a roadmap towards engineering climate-resilient plant immune systems.

plant biology↗

bioRxiv2022

Inhibitor of the nuclear transport protein XPO1 enhances the anticancer efficacy of KRAS G12C inhibitors in preclinical models of KRAS G12C mutant cancers

The identification of molecules that can bind covalently to KRAS G12C and lock it in an inactive GDP-bound conformation has opened the door to targeting KRAS G12C selectively. These agents have shown promise in preclinical tumor models and clinical trials. FDA has recently granted approval to sotorasib for KRAS G12C mutated non-small cell lung cancer (NSCLC). However, patients receiving these agents as monotherapy may not respond and generally develop drug resistance over time. This necessitates the development of multi-targeted approaches that can potentially sensitize tumors to KRAS inhibitors. We generated KRAS G12C inhibitor-resistant cell lines and observed that they exhibit sensitivity toward selinexor, a selective inhibitor of nuclear export protein exportin1 (XPO1), as a single agent. KRAS G12C inhibitor MRTX1257 in combination with selinexor suppressed the proliferation of KRAS G12C mutant cancer cell lines MiaPaCa-2 and NCI-H2122 in a synergistic manner. Moreover, combined treatment of selinexor with KRAS G12C inhibitors resulted in enhanced spheroid disintegration, reduction in the number and size of colonies formed by G12C mutant cancer cells. A combination of selinexor with KRAS G12C inhibitors potentiated the inhibition of KRAS expression in MiaPaCa-2 cells. NF-kB protein expression was also markedly reduced by selinexor and MRTX1257 combination. In an in vivo KRAS G12C cell-derived xenograft model, oral administration of a combination of selinexor and sotorasib was demonstrated to reduce tumor burden and enhance survival. In conclusion, we have shown that the nuclear transport protein XPO1 inhibitor can enhance the anticancer activity of KRAS G12C inhibitors in preclinical cancer models. SignificanceIn this study, combining nuclear transport inhibitor selinexor with KRAS G12C inhibitors has resulted in potent antitumor effects in preclinical cancer models. This can be an effective combination therapy for cancer patients that do not respond or develop resistance to KRAS G12C inhibitor treatment.

cancer biology↗

bioRxiv2020

Non-apoptotic enteroblast-specific role of the initiator caspase Dronc for development and homeostasis of the Drosophila intestine

The initiator caspase Dronc is the only CARD-domain containing caspase in Drosophila and is essential for apoptosis. Here, we report that homozygous dronc mutant adult animals are short-lived due to the presence of a poorly developed, defective and leaky intestine. Interestingly, this mutant phenotype can be significantly rescued by enteroblast-specific expression of dronc+ in dronc mutant animals, suggesting that proper Drone function specifically in enteroblasts, one of four cell types in the intestine, is critical for normal development of the intestine. Furthermore, enteroblast-specific knockdown of dronc in adult intestines triggers hyperplasia and differentiation defects. These enteroblast-specific functions of Drone do not require the apoptotic pathway and thus occur in a non-apoptotic manner. In summary, we demonstrate that an apoptotic initiator caspase has a very critical non-apoptotic function for normal development and for the control of the cell lineage in the adult midgut and therefore for proper physiology and homeostasis. HighlightsO_LIdronc mutants die from a fragile and leaky intestine C_LIO_LIdronc has a critical function in enteroblasts of the intestine C_LIO_LIdronc controls proliferation and differentiation in the intestine C_LIO_LIdronc performs these functions in an apoptosis-independent (non-apoptotic) manner C_LI

cell biology↗

bioRxiv2020

Toll-9 interacts with Toll-1 to mediate a feedback loop during apoptosis-induced proliferation in Drosophila

Drosophila Toll-1 and all mammalian Toll-like receptors regulate innate immunity. However, the functions of the remaining eight Toll-related proteins in Drosophila are not fully understood. Here, we show that Drosophila Toll-9 is necessary and sufficient for a special form of compensatory proliferation after apoptotic cell loss (undead apoptosis-induced proliferation (AiP)). Mechanistically, for AiP, Toll-9 interacts with Toll-1 to activate the intracellular Toll-1 pathway for nuclear translocation of the NF-{kappa}B-like transcription factor Dorsal which induces expression of the pro-apoptotic genes reaper and hid. This activity contributes to the feedback amplification loop that operates in undead cells. Given that Toll-9 also functions in loser cells during cell competition, we define a general role of Toll-9 in cellular stress situations leading to the expression of pro-apoptotic genes which trigger apoptosis and apoptosis-induced processes such as AiP. This work identifies conceptual similarities between cell competition and AiP.

cell biology↗