The MSCA action included 4 work packages (WPs). WP1 determined the role of Stt3A and OSTγ (two components of OST complex) during Drosophila development, as a model of OST-linked diseases. The results indicate that of Stt3A and OSTγ (the fly homolog of human STT3A and TUSC3, respectively) are essential genes during Drosophila development and both genes are required early to ensure animal survival. In particular, adult lethality is likely ascribed to their loss in neurons and mesodermal cells with a special dependency on BMP signaling. WP2 sought to determine the molecular basis for the regulation of fly BMP signaling by Stt3A and OSTγ. The main results indicate that OSTγ is required in fly midgut for ensuring BMP signaling. Its role is to mask the N-glycosylation sites in the mature domain of Dpp (the fly homolog of human BMP4) and prevents its glycosylation. WP3 validated in a mammalian cell model and OST-linked diseases the results obtained in the OST-disease fly model. The main results provide pieces of evidence for the molecular mechanism of TUSC3 function in BMP signaling. Specifically, upon loss of TUSC3 misfolded BMP4 molecules accumulate in the ER upstream of the folding quality control machinery. Based on the observations, I envisage that TUSC3 could be a part of regulatory machinery that shunts polypeptides that cannot properly be folded, perhaps because their abundance saturates the folding machinery, toward ERAD degradation. In this model, the role of TUSC3 could be to mask the glycosylation site on the polypeptide by forming a cysteine bond, as previously reported. This event could then induce Malectin to bind the un- or mis-glycosylated substrate to ultimately send it to the retrotraslocon. In WP4, the Fellow implemented his research skills in particular sharing knowledge with the host organization in particular with the supervisor’s group, Thomas Vaccari laboratories. Moreover, the Fellow learned how to manage reagent offers and the interface with vendors and chemical and biological companies with the help of the head of the Project Offices and department offices of the University of Milan. By attending weekly group meetings with the Vaccari group and monthly presenting his data, the Fellow implemented his communication skills in a knowledge-building environment. This all allowed the Fellow to join 5 conferences (3 as invited speakers), 8 workshops, advice and mentor two full-time Master Degree students, and attend several technical trainings.
