Role of galectin-1, RAB2A, RAB5A, RAB17 and RAB18 on CD8 t cell-mediated cytotoxicity

• Grant number: 14/16352-6
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2014
• End date: October 31, 2016
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: João Gustavo Pessini Amarante Mendes
• Grantee: João Gustavo Pessini Amarante Mendes
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Secretory granule exocytosis of CD8 T cells (also known as CTL - cytotoxic T lymphocyte) or NK cells (Natural Killer) is one of the most important weapons we have against intracellular pathogens and tumor cells. Despite the intense research on the development, activation and function of these cells, our understanding of the molecular mechanisms involved in directed degranulation, target cell killing and survival of the cytotoxic cells remain incomplete. In particular, the composition of CTL and NK lytic granules remains elusive. It is know that perforin and granzymes, especially granzyme B, are crucial to induce apoptosis in target cells. Moreover, other cytotoxic granule components are responsible for the traffic (degranulation) and maintenance of the vesicle structure, including proper protein folding and transport. Importantly, deficiency in proteins involved in vesicle traffic constitutes the bases for a variety of diseases, such as Griscelli, Hermansky-Pudlak and Chediak-Higashi Syndromes. Previous result from our group identified by proteomic analysis dozens of new CTL granule proteins, beside most of the previously ascribed, such as perforin and all the granzymes. Among the new proteins, we identified galectin-1 (GAL-1), a lectin that recognize beta-galactosides and participates in a variety of biological processes, including adaptive immune responses. It is well known that galectins can interact with cell surface glycans and, thereby, modulate the production of certain cytokines and other mediators, adhesion, cell death, chemotaxis and endocytosis. However, it is believed that GAL-1 secretion involves a non-conventional pathway and was never associated with any sort of granules. Our findings point out to a novel secretory pathway in the context of a CTL response, where GAL-1 would be secreted in combination with other cytotoxic granule proteins. This way, we believe GAL-1 may play a role in the effector mechanism of cytotoxic cells. Beside GAL-1, and other novel proteins, we found out the presence of RAB2a, a RAB5a, a RAB17 e a RAB18. RABs are a family of proteins involved in intracellular vesicle traffic. Although many different publications have already described important roles for RABs, there are very few relating these proteins with movement of cytotoxic granules; none of them dealing with RAB2a, a RAB5a, a RAB17 e a RAB18. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CLEMENTE, TIAGO; VIEIRA, NARCISIO J.; CERLIANI, JUAN P.; ADRAIN, COLIN; LUTHI, ALEXANDER; DOMINGUEZ, MARIANA R.; YON, MONICA; BARRENCE, FERNANDA C.; RIUL, THALITA B.; CUMMINGS, RICHARD D.; et al. Proteomic and functional analysis identifies galectin-1 as a novel regulatory component of the cytotoxic granule machinery. CELL DEATH & DISEASE, v. 8, DEC 2017. (14/16352-6)