Trans-endocytosis elicited by nectins transfers cytoplasmic cargo, including infectious material, between cells

Abstract

Here, we show that cells expressing the adherens junction protein nectin-1 capture nectin-4-containing membranes from the surface of adjacent cells in a trans-endocytosis process. We find that internalized nectin-1-nectin-4 complexes follow the endocytic pathway. The nectin-1 cytoplasmic tail controls transfer: its deletion prevents trans-endocytosis, while its exchange with the nectin-4 tail reverses transfer direction. Nectin-1-expressing cells acquire dyelabeled cytoplasmic proteins synchronously with nectin-4, a process most active during cell adhesion. Some cytoplasmic cargo remains functional after transfer, as demonstrated with encapsidated genomes of measles virus (MeV). This virus uses nectin-4, but not nectin-1, as a receptor. Epithelial cells expressing nectin-4, but not those expressing another MeV receptor in its place, can transfer infection to nectin-1expressing primary neurons. Thus, this newly discovered process can move cytoplasmic cargo, including infectious material, from epithelial cells to neurons. We name the process nectin-elicited cytoplasm transfer (NECT). NECT-related trans-endocytosis processes may be exploited by pathogens to extend tropism. This article has an associated First Person interview with the first author of the paper.

Family-wide Structural and Biophysical Analysis of Binding Interactions among Non-clustered δ-Protocadherins

“…The limited heterophilic responses observed between d2-protocadherins produced far lower responses than homophilic binding, and thus their physiological significance is less clear. Heterophilic interactions, commonly found for protein families that function primarily in adhesion, can play a role at boundaries between different cell types sharing a single family member (Basu et al, 2018;Brasch et al, 2018;Generous et al, 2019;Labernadie et al, 2017;Togashi et al, 2011;Volk et al, 1987), or in refining celllevel interaction specificity when co-expressed (Carrillo et al, 2015;Cosmanescu et al, 2018;Patel et al, 2006;Xu et al, 2018). As described above, d-protocadherins are often coexpressed in the same cell (Etzrodt et al, 2009), and effects of d-protocadherin co-expression on cell-interaction specificity have been demonstrated in cell aggregation experiments (Bisogni et al, 2018;Pederick et al, 2018).…”

Viral and host heterogeneity and their effects on the viral life cycle

“…A broad swath of pathogenic viruses reportedly hijack TNTs, including retroviruses, herpesviruses, vaccinia virus, flaviviruses, human metapneumovirus (HMPV), measles virus and IAVs [3][4][5][113][114][115][116][117][118][119][120][121][122][123] . The mechanism through which each of these viruses traverses a nanotubular bridge appears to be distinct, although the use of the actinmyosin cytoskeletal machinery for trafficking along a TNT is common for many 3,4,114,115 .…”

Receptor-mediated cell entry of paramyxoviruses: Mechanisms, and consequences for tropism and pathogenesis

“…A neural receptor accounting for these pathologies has been sought but not yet identified (80). Alternative mechanisms that may account for neuro-invasion include MeV delivery to the brain by SLAM-expressing infected immune cells and a newly discovered form of cytoplasm transfer occurring between nectin-4 -expressing epithelial cells and nectin-1expressing neurons (81).…”