Involvement of the TRPML Mucolipin Channels in Viral Infections and Anti-viral Innate Immune Responses.

Abstract

The TRPML channels (TRPML1, TRPML2, and TRPML3), belonging to the mucolipin TRP subfamily, primary localize to a population of membrane-bonded vesicles along the endocytosis, and exocytosis pathways. Human viruses enter host cells by plasma membrane penetration or by receptor-mediated endocytosis. TRPML2 enhances the infectivity of a number of enveloped viruses by promoting virus vesicular trafficking and escape from endosomal compartment. TRPML2 expression is stimulated by interferon and by several toll like receptor (TLR) activators, suggesting a possible role in the activation of the innate immune response. Noteworthy, TRPML1 plays a major role in single strand RNA/DNA trafficking into lysosomes and the lack of TRPML1 impairs the TLR-7 and TLR-9 ligand transportation to lysosomes resulting in decreased dendritic cell maturation/activation and migration to the lymph nodes. TRPML channels are also expressed by natural killer (NK) cells, a subset of innate lymphocytes with an essential role during viral infections; recent findings have indicated a role of TRPML1-mediated modulation of secretory lysosomes in NK cells education. Moreover, as also NK cells express TLR recognizing viral pattern, an increased TLR-mediated activation of cytokine production can be envisaged, suggesting a dual role in the NK cell-mediated antiviral responses. Overall, TRPML channels might play a double-edged sword in resistance to viral infections: on one side they can promote virus cellular entry and infectivity; on the other side, by regulating TLR responses in the various immune cells, they contribute to enhance antiviral innate and possibly adaptive immune responses.