How much or little linear ubiquitination makes our metabolism sick? - The role of linear ubiquitination in inflammatory processes in (dys)functional adipose tissue

• Applicant: Dr. Julia Zinngrebe
• Subject Area: Pediatric and Adolescent Medicine
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 520584003

Ubiquitination is a post-translational modification process of proteins that regulates a variety of different processes in human cells. The linear ubiquitin chain assembly complex (LUBAC) is the only protein complex known to date in mammalian cells that is capable of synthesizing linear ubiquitin chains. While ubiquitin chains are formed by E3 ubiquitin ligases, they are degraded by enzymes called deubiquitinases (DUBs). The OTU deubiquitinase with linear linkage specificity (OTULIN) was identified in 2013 and specifically and exclusively cleaves linear ubiquitin chains. Linear ubiquitin chains play a key role in the regulation of signaling pathways involved in inflammatory processes of innate and adaptive immunity. Dysregulation of linear ubiquitin chains is associated with numerous pathologies. Autoinflammation is a recurrent symptom in this regard. Deficiency of linear ubiquitin chains leads to glycogenosis in affected patients, while the excess of linear ubiquitin chains leads to the so-called OTULIN-Related Autoinflammatory Syndrome (ORAS). ORAS patients suffer from, among other things, inflammation of the subcutaneous adipose tissue and may develop hepatic steatosis. The liver and adipose tissue are significantly involved in the regulation of human energy metabolism and its homeostasis. Based on this relationship, we think that linear ubiquitination is critically involved in the regulation of adipose tissue metabolism and inflammation. The basic hypothesis of this project is that linear ubiquitination plays an essential role in the regulation of inflammatory processes in (dys)functional adipose tissue. On this basis, we pursue the following goals: 1. to characterize the function of linear ubiquitination in adipocyte metabolism, 2. to investigate whether linear ubiquitination influences adipogenesis and browning of adipose tissue, 3. to understand how linear ubiquitin controls inflammation in adipose tissue, and 4. to investigate pathogenic mutations that disrupt linear ubiquitination in patients for their impact on adipose tissue metabolism and inflammation. Understanding how linear ubiquitination regulates basal metabolic processes in adipose tissue will help to understand pathomechanisms in obesity, adipose tissue inflammation, and associated comorbidities. Obesity has become a global problem, especially because the associated comorbidities of obesity lead to high morbidity and mortality. Therefore, a better understanding of the underlying pathomechanisms is essential for the development of therapeutic approaches.

• DFG Programme: Research Grants
• Co-Investigator: Professorin Dr. Pamela Fischer-Posovszky