Biology subjects

Hennrich, M. L.

Publications and source records attributed to Hennrich, M. L..

5 recordsLinked to original sources

bioRxiv2023

A system-wide analysis of lipid transfer proteins delineates lipid mobility in human cells

Lipid transfer proteins (LTPs) maintain the specialised lipid compositions of biological membranes, and many are associated with disease. In eukaryotes, they support organellar functions by transporting lipids between compartmentalised metabolic pathways. However, for the majority of the hundreds of human LTPs, the cargoes remain unknown. We combined biochemical, lipidomic and computational methods to characterize LTP-lipid complexes assembled in cellulo and in an in vitro biochemical assay. We identified bound lipids for about half of the LTPs analysed, and confirmed known cargoes, while discovering new ones for most LTP families. The data represents a systematic resource that captures the general principles of non-vesicular lipid transport in humans. The specificity of LTPs for lipids involves not only the recognition of specific head groups, but also of specific acyl chains. This selectivity defines lipid species within a lipid class with different metabolic or functional fates. The generalised ability of LTPs to form complexes with more than one class of lipids delineates new relationships between lipids and regulatory mechanisms that may contribute to the coordination of metabolism between different organelles. This work represents a resource and a framework for further analyses in different cell types, in pathological states or following various cellular perturbations.

biochemistry↗

bioRxiv2023

CLICK-chemoproteomics and molecular dynamics simulation reveals pregnenolone targets and their binding conformations in Th2 cells

Pregnenolone (P5) is synthesized as the first bioactive steroid in the mitochondria from cholesterol. CD4+ and CD8+ immune cells synthesize P5 de novo, P5 in turn play important role in immune homeostasis and regulation. However, P5s biochemical mode of action in immune cells is still emerging. We envisage that revealing the complete spectrum of P5-target proteins in immune cells would have multifold applications, not only in basic understanding of steroids biochemistry in immune cells but also in developing new therapeutic applications. We employed a CLICK-enabled probe to capture P5-binding proteins in live Th2 cells. Subsequently, using high-throughput quantitative proteomics we identified the P5-interactome in CD4+ Th2 cells. Our study revealed P5s conserved mode of action in CD4+ and CD8+ immune cells. We identified novel proteins from mitochondrial and endoplasmic reticulum membranes to be the primary mediators of P5s biochemistry in CD4+ and CD8+ immune cells. Applying advanced computational algorithms, we were able to generate near-native maps of P5-protein key molecular interactions that can lead to successful designing of novel molecular therapeutics strategies.

immunology↗

bioRxiv2023

Nutritional stress-induced regulation of microtubule organization and mRNP transport by HDAC1 controlled α-tubulin acetylation

In response to nutritional stress, microtubules in cells of the Drosophila female germline are depleted from the cytoplasm and accumulate cortically. This triggers aggregation of mRNPs into large reticulated sponge bodies and oogenesis arrest. Here, we show that hyperacetylation of -tubulin at lysine 40 (K40) alters microtubule dynamics and sponge body formation. We found that depletion of histone deacetylase 1 (HDAC1) by RNAi phenocopies the nutritional stress response, causing hyperacetylation of -tubulin, as well as accumulation of maternally deposited mRNPs in reticulated sponge bodies. Using in vitro and in vivo studies, we identify HDAC1 as a direct regulator of -tubulin K40 acetylation status. In well-fed flies, HDAC1 maintains low levels of -tubulin acetylation, enabling the microtubule dynamics required for mRNP transport. Using quantitative phosphoproteomics we identify nutritional stress-induced changes in protein phosphorylation that act upstream of -tubulin acetylation, including phosphorylation of HDAC1 at S391, which reduces its ability to deacetylate -tubulin. These results reveal that Drosophila HDAC1 senses and relays the nutritional status, which regulates germline development through modulation of cytoskeleton dynamics.

developmental biology↗

bioRxiv2021

Enhancer-priming in ageing human bone marrow mesenchymal stromal cells contributes to immune traits

Bone marrow mesenchymal stromal cells (BMSCs) can differentiate into adipocytes and osteoblasts, and are important regulators of the haematopoietic system. Ageing associates with an increased ratio of bone marrow adipocytes to osteoblasts and immune dysregulation. Here, we carried out an integrative multiomics analysis of ATAC-Seq, RNA-Seq and proteomics data from primary human BMSCs in a healthy cohort age between 20 - 60. We identified age-sensitive elements uniquely affecting each molecular level where transcription is mostly spared, and characterised the underlying biological pathways, revealing the interplay of age-related gene expression mechanism changes spanning multiple gene regulatory layers. Through data integration with enhancer-mediated gene regulatory network analysis, we discovered that enhancers and transcription factors influence cell differentiation potential in the ageing BMSCs. By combining our results with genome-wide association study data, we found that age-specific changes could contribute to common traits related to BMSC-derived tissues such as bone and adipose tissue, and to immune-related traits on a systemic level such as asthma. We demonstrate here that a multiomics approach is crucial for unravelling complex information, providing new insights on how ageing contributes to bone marrow- and immune-related disorders.

systems biology↗

bioRxiv2019

CLICK-enabled analogues reveal pregnenolone interactomes in cancer and immune cells

Pregnenolone (P5) promotes prostate cancer cell growth, and de novo synthesis of intratumoural P5 is a potential cause of development of castration-resistance. Immune cells can also synthesize P5 de novo. Despite its biological importance, little is known about P5s mode of actions, which appears to be context-dependent and pleiotropic. A comprehensive proteome-wide spectrum of P5-binding proteins that are involved in its trafficking and functionality remains unknown. Here, we describe an approach that integrates chemical biology for probe synthesis with chemoproteomics to map P5-protein interactions in live prostate cancer cells and murine CD8+ T cells. We subsequently identified P5-binding proteins potentially involved in P5-trafficking, and in P5s non-genomic action that may drive the promotion of castrate-resistance prostate cancer and regulate CD8+ T cell function. We envisage that this methodology could be employed for other steroids to map their interactomes directly in a broad range of living cells, tissues and organisms.

biochemistry↗