Project Details
Projekt
Defining the autophagy-mediated secretome and its impact during stage transitions in chronic liver disease
Applicant
Evangelos Kondylis, Ph.D.
Subject Area
Gastroenterology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 546585894
Passive release of damage-associated molecular patterns (DAMPs) from dying hepatocytes drives inflammatory liver disease progression and hepatocellular cancer. DAMP secretion, however, also occurs from intact cells upon various stress stimuli. Secretory autophagy is a pathway of unconventional secretion, which, in contrast to degradative autophagy that eliminates selected cargos in lysosomes, involves the direct or indirect release of the autophagosomal content into the extracellular milieu. In our previous work, we focused on the homeostatic role of autophagy in the liver, as well as the multiple functions of the autophagy receptor Sequestosome-1/p62, including the selection of secretory cargo. Our data also suggest that secretion of typical DAMPs, such as HMGB1, from stressed hepatocytes can be regulated by modulating autophagic flux. While autophagy-dependent secretion emerges as a potential mechanism for maintaining organ homeostasis and shaping inflammatory, fibrotic and tumour microenvironments, its role in liver physiology and disease is unclear. Project P04 aims to define the autophagy-mediated secretome released from hepatocytes and its impact on stage transitions in chronic liver disease. Specifically, our goals are: 1) to characterize the secretory autophagy dynamics and released cargo from hepatocytes in vitro and in vivo in mice expressing a GFP-LC3 reporter using 2-photon microscopy and proteomics, 2) to identify changes in autophagy-dependent secretome during stage transitions in mice with diet-induced metabolic dysfunction-associated steatohepatitis (MASH), 3) to validate the response evoked by autophagy-associated secretome on macrophages and precision-cut liver slices and 4) to evaluate the autophagy-dependent DAMP signature in plasma of patients with liver disease and cancer. Project P04 is conceptually integrated in the dangerhep consortium, including interactions with P01-P03 (comparison to secretomes associated with apoptosis, lethal and sublethal necroptosis), P06 (hepatic autophagy crosstalk to adipose tissue), P07 (secretory autophagy interaction with sphingolipid metabolism), and P08-P09 (impact of autophagy-dependent secretome on immune responses). Additionally, it involves strong methodological synergies with the dangerhep toolbox that are essential for its success, including intravital 2-photon microscopy (C01), proteomics and lipidomics (P05, P07), use of precision-cut liver slices (P03), immunophenotyping (P08-P09) and human biobanking (P08). Altogether, project P04 will address the contribution of secretory autophagy in DAMP release during stage transitions in chronic liver disease, and could reveal biomarkers whose expression may serve as surrogate for autophagy flux alterations in liver disease patients improving their stratification and expanding the therapeutic strategies.
DFG Programme
Research Units
