The majority of proteins secreted in the extracellular space follow a designated path that involves the endoplasmic reticulum, the Golgi complex and secretory vesicles that fuse with the plasma membrane. However, it is becoming apparent that some proteins follow an unconventional protein secretion path without a signal peptide for entry into the ER and Golgi pathway. The implicated mechanism is poorly defined and still under a lot of speculation. The EU-funded UNPROSEC project worked on fatty acid-binding protein 4 (FABP4), a cytoplasmic protein essentially expressed by adipocytes and elevated in obesity. Being unconventionally secreted, FABP4 controls glucose liver metabolism and promotes atherosclerosis and diabetes type 2 in mouse models. Its inhibition constitutes a valid strategy for the treatment of metabolic diseases. Therefore, understanding the mechanisms involved in FABP4 secretion is of fundamental importance for comprehending human metabolic diseases. UNPROSEC scientists investigated FABP4 secretion, giving particular emphasis on vesicular intermediates and proteins involved in the process. Biochemical and morphological analyses showed that FABP4 is transported from the cytosol to the extracellular space by vesicle carriers, independent of the classical secretory pathway and the autophagy process. Scientists observed that impairment of the endocytosis pathway stops FABP4 trafficking inside vesicle intermediates of the early endosomal compartment. Similarly, impairment of protein and membrane trafficking towards the lysosomes stops FABP4 transport inside vesicle carriers of the late endosomal compartment, in close proximity of lysosomes. Collectively, these findings indicated that FABP4 is transported via the endocytosis pathway, before it is released by exocytosis of secretory lysosomes. Overall, the outcome of the UNPROSEC study underlines the pleiotropic range of mechanisms involved in the unconventional secretion of proteins, underscoring the plasticity of the molecular machineries involved in membrane and protein trafficking. With respect to FABP4, the results of the project will help the design of future treatment strategies for various metabolic diseases.
Protein secretion, UNPROSEC, FABP4, endocytosis, lysosomes