Biology subjects

Short, A.

Publications and source records attributed to Short, A..

2 recordsLinked to original sources

bioRxiv2022

Interplay between LHCSR proteins and state transitions governs the NPQ response in intact cells of Chlamydomonas during light fluctuations.

Photosynthetic organisms use sunlight as the primary energy source to fix CO2. However, in the environment, light energy fluctuates rapidly and often exceeds saturating levels for periods ranging from seconds to hours, which can lead to detrimental effects for cells. Safe dissipation of excess light energy occurs primarily by non-photochemical quenching (NPQ) processes. In the model green microalga Chlamydomonas reinhardtii, photoprotective NPQ is mostly mediated by pH-sensing light-harvesting complex stress-related (LHCSR) proteins and the redistribution of light-harvesting antenna proteins between the photosystems (state transition). Although each component underlying NPQ has been documented, their relative contributions to the dynamic functioning of NPQ under fluctuating light conditions remains unknown. Here, by monitoring NPQ throughout multiple high light-dark cycles with fluctuation periods ranging from 1 to 10 minutes, we show that the dynamics of NPQ depend on the frequency of light fluctuations. Mutants impaired in the accumulation of LHCSRs (npq4, lhcsr1, and npq4lhcsr1) showed significantly less quenching during illumination, demonstrating that LHCSR proteins are responsible for the majority of NPQ during repetitive exposure to high light fluctuations. Activation of NPQ was also observed during the dark phases of light fluctuations, and this was exacerbated in mutants lacking LHCSRs. By analyzing 77K chlorophyll fluorescence spectra and chlorophyll fluorescence lifetimes and yields in a mutant impaired in state transition, we show that this phenomenon arises from state transition. Finally, we quantified the contributions of LHCSRs and state transition to the overall NPQ amplitude and dynamics for all light periods tested and show that both processes interact to facilitate NPQ during light fluctuations. We further assess the role of LHCSRs in cell growth under various periods of fluctuating light. These results highlight the dynamic functioning of photoprotection under light fluctuations and open a new way to systematically characterize the photosynthetic response to an ever-changing light environment. One sentence summaryThe roles of LHCSR and STT7 in NPQ vary with the light fluctuation period and duration of light fluctuation.

plant biology↗

bioRxiv2021

The immunophilin protein FKBPL and its peptide derivatives are novel regulators of vascular integrity and inflammation via NF-kappaB signaling

A breakdown in vascular integrity and excessive inflammation are hallmarks of serious pathological conditions including sepsis, acute respiratory distress syndrome (ARDs) and most recently, severe COVID-19. FK506 - binding protein like (FKBPL) is a member of the immunophilin protein superfamily with potent anti-tumor activity through inhibition of angiogenesis and cancer stemness. An FKBPL-based 23mer peptide, ALM201, displayed a good safety and pharmacokinetic profile in a Phase 1a oncology clinical trial and was subsequently designated orphan drug status by the FDA in ovarian cancer. Here we describe a novel role for FKBPL and its peptides in regulating vascular integrity and cytokine production though modulating NF-{kappa}B signaling. FKBPL knockdown promoted endothelial cell barrier permeability, which was further exacerbated upon stimulation with lipopolysaccharide (LPS) and accompanied by increased expression of TNF mRNA and phosphorylation of p65(RelA). Whilst treatment with the FKBPL based pre-clinical peptide, AD-01, increased VE-cadherin endothelial tight junctions following LPS stimulation. Bone marrow derived macrophages (BMDM) from FKBPL haploinsufficient mice (Fkbpl+/-) also demonstrated increased phosphorylation of p65(RelA) in response to LPS stimulation compared to wild-type mice. Furthermore, treatment with AD-01 inhibited p65(RelA) phosphorylation following LPS stimulation resulting in reduced NF-{kappa}B target gene expression and proinflammatory cytokine production. In an in vivo LPS survival model, Fkbpl+/- mice have reduced survival compared to wild-type mice. Moreover, treatment of wild-type mice with the clinical FKBPL-based peptide, ALM201, following LPS injection resulted in a 100% survival rate in mice at experimental endpoint, as well as an abrogation of production of pro-inflammatory cytokines, TNF and IL-6, in peritoneal lavage washings. Analysis of human genetic biobanks found an association between common genetic variants associated with FKBPL and traits associated with inflammatory disorders such as psoriasis, rheumatoid arthritis and high lymphocyte count. In summary, for the first time, we describe a novel role for FKBPL as a regulator of inflammation and vascular integrity through modulating NF-{kappa}B signaling and FKBPL based therapies demonstrate potent anti-inflammatory activity.

immunology↗