Investigating GRASP Structure-Activity Relationship, Supramolecular Arrangements and Interaction Partners in Unconventional Secretion and Possible Implications for Orthobunyavirus Assembly.

• Grant number: 25/19374-5
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: October 01, 2025
• End date: September 30, 2028
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Luis Lamberti Pinto da Silva
• Grantee: Juan Oswaldo Concha Casaverde
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 23/04532-9 - The exquisite biophysics of the unconventional protein secretion: old and new looks to old and new problems, AP.TEM

Abstract

Unconventional protein secretion (UPS) is a cellular process that bypasses the classical endoplasmic reticulum-Golgi pathway and enables the direct release of proteins into the extracellular space. While the precise molecular details of UPS are still being elucidated, these mechanisms collectively enable the release of cytokines, growth factors, enzymes, and signaling molecules that play crucial roles in intercellular communication and tissue homeostasis in health and disease. Aberrant unconventional protein secretion has been associated with several pathological conditions, including neurodegenerative disorders, cancer, and viral infections (Jacopo, 2023). During viral infections, cells can exploit UPS to release antiviral factors that contribute to the innate immune response against viral pathogens. On the other hand, viruses themselves can hijack UPS mechanisms to promote their replication, dissemination, and evasion of host immune defenses. The Golgi reassembly stacking protein (GRASP) family of proteins has emerged as a key regulator of UPS. GRASP proteins localize to the Golgi apparatus and contribute to the formation of specialized membrane domains involved in UPS. This project aims to: (1) elucidate the functional role of specific structural domains of GRASP in UPS, (2) discover new GRASP interaction partners that may contribute to GRASP activities, and (3) investigate whether the supramolecular arrangements of GRASP (fibrils or biocondensates) observed in vitro are functionally relevant in vivo. In addition, we initiate an investigation into the potential role of GRASP in the replication of Oropouche virus (OROV), an orthobunyavirus that causes a medically important arbovirosis in Brazil. Our previous research shows that OROV assembles at Golgi-derived membranes (Barbosa et al., 2018) and may exit cells through a mechanism that resembles secretory autophagy/UPS (our unpublished data). Exploring the intricate molecular interactions and functional dynamics of GRASP proteins in UPS may uncover new targets for therapeutic intervention against Bunyavirus infections.