M-Sec facilitates intercellular transmission of HIV-1 through multiple mechanisms

Abstract

Background HIV-1 promotes the formation of tunneling nanotubes (TNTs) that connect distant cells, aiding cell-to-cell viral transmission between macrophages. Our recent study suggests that the cellular protein M-Sec plays a role in these processes. However, the timing, mechanism, and to what extent M-Sec contributes to HIV-1 transmission is not fully understood, and the lack of a cell line model that mimics macrophages has hindered in-depth analysis. Results We found that HIV-1 increased the number, length and thickness of TNTs in a manner dependent on its pathogenic protein Nef and M-Sec in U87 cells, as observed in macrophages. In addition, we found that M-Sec was required not only for TNT formation but also motility of U87 cells, both of which are beneficial for viral transmission. In fact, M-Sec knockdown in U87 cells led to a significantly delayed viral production in both cellular and extracellular fractions. This inhibition was observed for wild-type virus, but not for a mutant virus lacking Nef, which is known to promote not only TNT formation but also migration of infected macrophages. Conclusions By taking advantage of useful features of U87 cells, we provided evidence that M-Sec mediates a rapid and efficient cell–cell transmission of HIV-1 at an early phase of infection by enhancing both TNT formation and cell motility.

The Functions, Methods, and Mobility of Mitochondrial Transfer Between Cells

“…The components of the exocyst complex interact with several small GTPases (Rho1, Rho3, Cdc42, and RalA) to promote actin cytoskeletal remodeling, which is closely related to the function of the exocyst complex (69,71,72). The exocyst complex also participates in the formation of TNTs, and this process is controlled by M-Sec, a protein that has been proven to control the formation of TNTs (73,74). M-Sec can promote the assembly of the exocyst complex and interact with it, as well as with RalA (or Cdc42), leading to actin cytoskeleton remodeling, which is the key step of TNT formation (75).…”

Cellular and molecular actors of myeloid cell fusion: podosomes and tunneling nanotubes call the tune

“…Another potential role for TNTs in cell-to-cell fusion concerns HIV-1 infection of macrophages [ 111 , 197 , 206 , 207 ], which are prone to form MGCs (see “ Introduction ”). In this context, we revealed a correlation between the formation of TNTs at the early stages of HIV-1 infection of human macrophages and the extent of the fusion later on [ 57 , 111 , 195 , 197 , 208 ].…”

“…In this context, we revealed a correlation between the formation of TNTs at the early stages of HIV-1 infection of human macrophages and the extent of the fusion later on [ 57 , 111 , 195 , 197 , 208 ]. In terms of molecular actors, M-Sec mediates rapid and efficient cell-to-cell transmission of HIV-1 at an early phase of infection by enhancing both cell motility, TNT formation, and number of nuclei per infected macrophages [ 207 ]. Finally, Cx43 localizes at the tip of close-ended TNTs formed between HIV-infected macrophages, suggesting that stabilization of long-range gap junction-dependent communication could favor HIV-1 transfer [ 206 ].…”

M-Sec induced by HTLV-1 mediates an efficient viral transmission

“…We recently demonstrated that M-Sec promotes cell-to-cell infection of HIV-1 [ 8 , 9 ]. Small molecule compound that inhibits M-Sec-induced membrane protrusions reduced HIV-1 production in monocyte-derived macrophages [ 8 ].…”

“…Small molecule compound that inhibits M-Sec-induced membrane protrusions reduced HIV-1 production in monocyte-derived macrophages [ 8 ]. Moreover, the knockdown of M-Sec retarded HIV-1 production in U87 glioma cells [ 9 ], a widely-used HIV-1 target cell line. As M-Sec inhibition or knockdown reduces membrane protrusions and cell migration in these cells [ 8 , 9 ], M-Sec appears to contribute to the initial phase of HIV-1 transmission by enhancing membrane protrusions and cell migration.…”