Communication of mechanical cues to the stress response in epidermal cells

• Applicant: Professorin Dr. Carien Niessen
• Subject Area: Cell Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 388932620

The skin epidermis is exposed on a daily basis to external forces such as stretching or compression. The cells of the epidermis, keratinocytes, need to sense, communicate and respond to this mechanical challenge to maintain its barrier function to prevent e.g. infections or water loss. Adhesive junctions such as the cadherin-based adherens junctions and the actin cytoskeleton are key sensors and transducers of mechanical signals, and, as shown by us and others, important mediators of mechanical stress resistance. However, how junctions maintain healthy proteostasis to promote mechanical resistance is not known. We recently found that the polarity protein aPKC coordinates the dynamics of adhesive junctions and their associated cytoskeletal systems to control cell mechanics. Multilayered proteomics also showed that mammalian aPKCs interact with, phosphorylate and/or control protein levels of several chaperone proteins including BAG3 and HSPB8 previously implicated in mechanical stress-induced autophagy. Moreover, p62, a protein that targets cargo to autophagosomes, is a prominent direct binding partner of aPKCs, and loss of aPKClambda promotes autophagy. We thus hypothesize that sensing of mechanical force spatially regulates aPKC activity to coordinate of BAG3-dependent autophagy of damaged mechanosensitive proteins with AJ dynamics necessary to resist stress and maintain short and long-term tissue function. We will test this hypothesis in the epidermis using a unilateral stretch devise and micropatterns to apply mechanical stress to primary control and mutant keratinocytes, in addition to using in vivo mouse models. In close collaborations within this research unit we will investigate (a) the role of BAG3 and P62-dependent autophagy in mechanical stress response (B) define how aPKC regulates mechanical stress induced BAG3-dependent autophagy and junctional proteostasis and (C) examine physiological and pathological consequences of impaired mechanical stress responses. Together these studies will define how cells respond to mechanical stress to maintain tissue integrity, and whether healthy proteostasis of mechanosensitive units such as adherens junctions is essential for stress resistance.

• DFG Programme: Research Units
• Subproject of: FOR 2743: Mechanical Stress Protection