Biology subjects

Krebiehl, C.

Publications and source records attributed to Krebiehl, C..

2 recordsLinked to original sources

bioRxiv2026

Acute lysosome repositioning reveals functional and proteomic adaptations

Lysosomes exhibit spatial heterogeneity, but establishing causal relationships remains challenging with existing relocalization strategies. We present a modular toolkit that rapidly repositions lysosomes on demand by recruiting inducible motors. This decouples the location of organelles from systemic stress. We demonstrate that peripheral lysosomes adapt quickly by exhibiting luminal alkalinization and reduced proteolytic capacity. Furthermore, peripheral sequestration impairs autophagic flux by creating a spatial "trafficking bottleneck". We use this system to provide an unbiased proteomic characterization of spatially distinct lysosomal populations using mass spectrometry. Our findings reveal a distinct set of proteins and complexes that are spatially partitioned between perinuclear and peripheral lysosomes. Perinuclear lysosomes are configured for metabolic recycling. They have a high density of V1 V-ATPase subunits and contain the nucleoside transporter SLC29A3. Conversely, peripheral lysosomes serve as secretory outposts that are enriched in cathepsin Z and the SPG11/SPG15/AP5 complex. These validated cell lines and extensive datasets provide a flexible framework for investigating the functional specialization of different lysosome populations.

cell biology↗

bioRxiv2022

Homeostatic feedback between lysosomal mTORC1 and mTORC2-AKT signaling controls nutrient uptake in brown adipose tissue

In brown adipose tissue (iBAT), the balance of lipid/glucose uptake and lipolysis is regulated by insulin signaling. Downstream of the insulin receptor, PDK1 and mTORC2 phosphorylate AKT, which activates glucose uptake and lysosomal mTORC1 signaling. The latter requires the late endosomal/lysosomal adaptor and MAPK and mTOR activator (LAMTOR/Ragulator). Deletion of LAMTOR2 (and thereby loss of the LAMTOR complex) in mouse adipocytes resulted in insulin-independent AKT hyperphosphorylation in iBAT, causing increased glucose and fatty acid uptake as evidenced by massively enlarged lipid droplets. As LAMTOR2 was essential for the upregulation of de novo lipogenesis, LAMTOR2 deficiency triggered exogenous glucose storage as glycogen in iBAT. These effects are cell autonomous, since AKT hyperphosphorylation was reversed by PI3K inhibition or by deletion of the mTORC2 component Rictor in LAMTOR2-deficient mouse embryonic fibroblasts. We identified a homeostatic circuit connecting LAMTOR-mTORC1 signaling with PI3K-mTORC2-AKT signaling downstream of the insulin receptor to maintain iBAT metabolism.

cell biology↗