The RXFP3‐GIT2 signaling system represents a potential multidimensional therapeutic target in age‐related disorders
Authors: van Gastel Jaana , Hendrickx Jhana , Leysen Hanne , Luttrell Louis M. , Lee Mi‐Hye M. , Azmi Abdelkrim , Janssens Jonathan , Maudsley Stuart 
Published: June 2021

Pathological aspects of the hyper‐complex aging process potently control the generation of neurodegenerative diseases, such as Alzheimer's or Parkinson's disease. Pathological aging and neurodegeneration are share many functional commonalities, i.e. progressive loss of cell stress resilience, oxidative DNA damage and metabolic dysfunction. This loss of stress resistance, results in the accumulation of damage, leading to systemic dysfunction and eventual cell death.It is currently conceptualized that complex physiological process, such as aging, are likely controlled through hierarchical coordination of focused signaling systems by ‘hub’ or ‘keystone’ proteins. These master‐regulator proteins have the ability to coordinate responses to dynamic molecular events through coherent organization of protein‐protein interactions with multiple distinct partners, bridging multiple signaling pathways and coordinating multisystem processes, such as aging. G protein‐coupled receptor kinase interacting protein 2 (GIT2) has been identified as a keystone protein in neurometabolic aging: GIT2 functionality is strongly associated with oxidative stress, DNA damage, metabolic dysfunction, immunesenescence and lifespan alterations. As a G protein‐coupled receptor (GPCR) interacting protein, it is however possible to control this protein through a proxy modulator. It has long been established that GPCR activity influencing the expression levels of their interacting/signaling proteins – thus creating a self‐reinforcing signaling system. Transcriptomic analysis of the GIT2 knockout mouse tissues, showed that one GPCR was consistently downregulated in the absence of GIT2, namely Relaxin Family Peptide 3 receptor (RXFP3). The RXFP3 receptor demonstrates multiple functional synergies with GIT2, i.e. glucose metabolism regulation and responsiveness to oxidative stress and stress resilience. Using an unbiased approach to generate comprehensive in cellula activity signatures as well as investigation of functional RXFP3‐interactomes we found strong evidence for RXFP3 roles in DNA damage repair, oxidative stress management, cell cycle arrest control, and glucose metabolism functionalities. These data support the existence of a tight functional synergy between RXFP3 and GIT2 – potentially via direct signaling association. We confirmed this functional interaction using co‐immunoprecipitation, microscopy, and bioluminescence resonance energy transfer (BRET). As RXFP3 expression alteration should be able to affect GIT2 expression –thus reinforcing this signaling unit, we also also demonstrated expression co‐regulation of both partners. Lastly, we investigated RXFP3 expression in a mouse model for age‐associated neurodegeneration (Granulin KO mice) – as with GIT2 expression in aging we found RXFP3 increases in expression with age and neurodegeneration. We hypothesize that age‐related stresses reinforce a tight functional association between RXFP3 and GIT2, thus forging an important therapeutic target system that regulates cellular degradation and controls disease etiology.Support or Funding InformationFWO‐Odysseus and FWO Travel GrantThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.