Wetzel, C. | bioRxiv Science

bioRxiv2022

MAP1LC3C regulates lysosomal exocytosis and induces zinc reprogramming in renal cancer cells

MAP1LC3C (LC3C) is a member of the microtubule associated family of proteins that are essential in the formation of autophagosomes and lysosomal degradation of cargo. LC3C has tumor suppressing activity and its expression is dependent on kidney cancer tumor suppressors, such as VHL and FLCN. Recently we demonstrated that LC3C autophagy is regulated by noncannonical upstream regulatory complexes and targets for degradation postdivision midbody rings associated with cancer cells stemness. Here we show that loss of LC3C leads to peripheral positioning of the lysosomes and lysosomal exocytosis (LE) in a subset of cells. This process is independent of the autophagic activity of LC3C. Analysis of isogenic cells with low and high LE shows substantial transcriptomic reprogramming with altered expression of Zn-related genes and activity of Polycomb Repressor Complex 2 (PRC2), accompanied by a robust decrease in intracellular Zn. Metabolomic analysis revealed alterations in amino acid steady-state levels. Cells with augmented LE show tumor initiation properties and form aggressive tumors in xenograft models. Immunocytochemistry identified high levels of LAMP1 on the plasma membrane of cancer cells in human ccRCC and reduced levels of Zn, an indication that LE is a frequent event in ccRCC, potentially contributing to the loss of Zn. Overall, these data indicate that an important tumor suppressing activity of LC3C is contributing to the reprogramming of lysosomal activity and Zn metabolism with implication for epigenetic remodeling in a subpopulation of tumor propagating properties of cancer cells.

cell biology↗

bioRxiv2020

Implementing the precautionary approach into fisheries management: Making the case for probability-based harvest control rules

The precautionary approach to fisheries management advocates for risk-averse management strategies that include biological reference points as well as decision rules and account for scientific uncertainty. In this regard, two approaches have been recommended: (i) harvest control rules (HCRs) with threshold reference points to safeguard against low stock biomass, and (ii) the P* method, a probability-based HCR that reduces the catch limit as a function of scientific uncertainty (i.e. process, model, and observation uncertainty). This study compares the effectiveness of these precautionary approaches in recovering over-exploited fish stocks with various life-history traits and under a wide range of levels of scientific uncertainty. We use management strategy evaluation based on a stochastic, age-based operating model with quarterly time steps and a stochastic surplus production model. The results show that the most effective HCR includes both a biomass threshold as well as the P* method, and leads to high and stable long-term yield with a decreased risk of low stock biomass. For highly dynamics stocks, management strategies that aim for higher biomass targets than the traditionally used BMSY result in higher long-term yield. This study makes the case for probability-based HCRs by demonstrating their benefit over deterministic HCRs and provides a list of recommendations regarding their definition and implementation.

ecology↗