Biology subjects

Sloan, K.

Publications and source records attributed to Sloan, K..

3 recordsLinked to original sources

bioRxiv2021

Extremely thermophilic endospores germinate and metabolise organic carbon in sediments heated to above 80°C

Endospores of thermophilic bacteria are widespread in cold seabed environments where they remain dormant during initial burial in accumulating sediments. The temperature increase during sedimentation can be simulated in experimental heating of sediments, resulting in the temperature-dependent activation of different endospore populations from the microbial seed bank. Here we investigated the response of endospore populations to heating at extreme high temperature (80- 99{degrees}C). Metabolites for germination and organic matter degradation (dipicolinic acid and organic acids) revealed both endospore germination and subsequent metabolism at [≥]80{degrees}C. Endospore-forming Firmicutes with the genomic potential for organic carbon and nitrogen transformation were recovered by genome-resolved metagenomics. Genomes from Symbiobacteriales, Thermosediminibacteriales, Moorellales and Calditerricolales encode multiple mechanisms for high temperature degradation of sedimentary organic carbon and features of necromass that accumulate during sediment burial including saccharides, amino and nucleic acids. The results provide insight into the metabolism of novel carbon cycling microorganisms activated at high temperature, and suggest that extremely thermophilic Firmicutes dispersed in the ocean are poised to germinate in response to sediment heating during burial and transform a wide range of organic substrates.

microbiology↗

bioRxiv2020

Dynamic regulation of hierarchical heterogeneity in Acute Myeloid Leukemia serves as a tumor immunoevasion mechanism

Acute Myeloid Leukemia, a hematological malignancy with poor clinical outcome, is composed of hierarchically heterogeneous cells. We examine the contribution of this heterogeneity to disease progression in the context of anti-tumor immune responses and investigate whether these responses regulate the balance between stemness and differentiation in AML. Combining phenotypic analysis with proliferation dynamics and fate-mapping of AML cells in a murine AML model, we demonstrate the presence of a terminally differentiated, chemoresistant population expressing high levels of PDL1. We show that PDL1 upregulation in AML cells, following exposure to IFN{gamma} from activated T cells, is coupled with AML differentiation and the dynamic balance between proliferation, versus differentiation and immunosuppression, facilitates disease progression in the presence of immune responses. This microenvironment-responsive hierarchical heterogeneity in AML may be key in facilitating disease growth at the population level at multiple stages of disease, including following bone marrow transplantation and immunotherapy.

cancer biology↗

bioRxiv2020

Non-canonical autophagy drives alternative ATG8 conjugation to phosphatidylserine

Autophagy is a fundamental catabolic process essential for development, homeostasis and proper immune function 1. During autophagy, a cascade of ATG proteins target intracellular cargoes for lysosomal degradation and recycling 2. This pathway utilises a unique post-translational modification, the conjugation of ATG8 proteins to phosphatidylethanolamine (PE) at autophagosomes, which modulates cargo selection and maturation. ATG8 lipidation also occurs during non-canonical autophagy, a parallel pathway involving Single Membrane ATG8 Conjugation (SMAC) to endolysosomal compartments, which plays a key role in phagocytosis and other processes 3. It has been widely assumed that SMAC involves the same lipidation of ATG8 to PE, but this has yet to be formally tested. Here, we show that ATG8 undergoes alternative lipidation to phosphatidylserine (PS) during non-canonical autophagy/SMAC. Using mass spectrometry, we find that activation of SMAC, by pharmacological agents 4,5, or during non-canonical autophagy processes such as LC3-associated phagocytosis 6,7 and Influenza A virus infection 8, induces the covalent conjugation of ATG8 to PS, as well as PE. This alternative lipidation event is dependent on the ATG16L1 WD40 domain, and occurs at PS enriched endolysosomal membranes. Importantly, we find that the ATG8-PS and ATG8-PE adducts are differentially delipidated by isoforms of the ATG4 family, indicating significant molecular distinctions and mechanisms between these two species. Together, these results provide an important new insight into autophagy signalling, revealing an alternative form of the hallmark ATG8-lipidation event, so widely used to define and assay autophagy. Furthermore, ATG8-PS lipidation provides a specific molecular signature for non-canonical autophagy, uncovering a novel means of detecting and monitoring this emerging pathway.

cell biology↗