Lauren Sophie Johnson

• Lapao, Ana Sofia Da Silva; Johnson, Lauren Sophie; Moncho, Laura Cristina Trachsel; Rodgers, Samuel J; Singh, Sakshi & Ng, Matthew [Vis alle 9 forfattere av denne artikkelen] (2025). The RAB27A effector SYTL5 regulates mitophagy and mitochondrial metabolism. eLIFE. 14. doi: 10.7554/elife.105541. Fulltekst i vitenarkiv Vis sammendrag

  SYTL5 is a member of the Synaptotagmin-Like (SYTL) protein family that differs from the Synaptotagmin family by having a unique N-terminal Synaptotagmin homology domain that directly interacts with the small GTPase RAB27A. Several SYTL protein family members have been implicated in plasma membrane transport and exocytosis, but the specific function of SYTL5 remains unknown. We here show that SYTL5 is a RAB27A effector and that both proteins localise to mitochondria and vesicles containing mitochondrial material. Mitochondrial recruitment of SYTL5 depends on its interaction with functional RAB27A. We demonstrate that SYTL5-RAB27A positive vesicles containing mitochondrial material, autophagy proteins and LAMP1 form during hypoxia and that depletion of SYTL5 and RAB27A reduces mitophagy under hypoxia mimicking conditions, indicating a role for these proteins in mitophagy. Indeed, we find that SYTL5 interacts with proteins involved in vesicle-mediated transport and cellular response to stress and that its depletion compromises mitochondrial respiration and increases glucose uptake. Intriguingly, SYTL5 expression is significantly reduced in tumours of the adrenal gland and correlates positively with survival for patients with adrenocortical carcinoma.

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• Johnson, Lauren Sophie (2026). Lipid binding proteins in the regulation of autophagy and disease. Universitetet i Oslo. ISSN 9788234807701. Fulltekst i vitenarkiv Vis sammendrag

  Cells maintain homeostasis through autophagy, a pathway that carries out the removal of damaged or unwanted material and recycling of macromolecules under nutrient deprivation and stress. In autophagy, cargo is sequestered into double membrane vesicles known as autophagosomes that fuse with lysosomes containing enzymes that degrade the cargo. Autophagy can be a bulk degradation process or a selective one. Dysfunctional autophagy is implicated in the pathogenesis of many diseases, so elucidating its underlying molecular mechanisms is crucial for the development of new therapeutic strategies. In this thesis, we aimed to identify proteins that are novel regulators of autophagy, characterise their function and investigate their roles in disease. In paper I, we shortlisted protein candidates which bind membranes and have a link to disease, to assess whether they play a role in autophagy. Using a range of biochemical and imaging approaches, we demonstrated that the protein KRIT1 can interact directly with autophagy proteins. We also found that KRIT1 functions as a positive regulator of bulk and selective autophagy. In paper II, we characterised another membrane binding protein, SYTL5. We found that SYTL5 localises to the mitochondrial network through an interaction with RAB27A. The selective degradation of mitochondria, through mitophagy, was found to be positively regulated by SYTL5 and RAB27A. We also found that SYTL5 expression is significantly reduced in adrenal gland tumours and that low SYTL5 expression is associated with reduced survival of adrenocortical carcinoma patients. In paper III, we focus on the dipeptide repeat poly-GA protein aggregates that result from a mutation in C9orf72, associated with the neurodegenerative diseases ALS and frontotemporal dementia. We demonstrate that expression of poly-GA causes a reduction in autophagy, indicating a potential mechanism through which poly-GA aggregates contribute to neurodegeneration.

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