Exomer complex regulates protein traffic at the TGN through differential interactions with cargos and clathrin adaptor complexes

[EN] Protein sorting at the trans-Golgi network (TGN) usually requires the assistance of cargo adaptors. However, it remains to be examined how the same complex can mediate both the export and retention of different proteins or how sorting complexes interact among themselves. In Saccharomyces cerevisiae, the exomer complex is involved in the polarized transport of some proteins from the TGN to the plasma membrane (PM). Intriguingly, exomer and its cargos also show a sort of functional relationship with TGN clathrin adaptors that is still unsolved. Here, using a wide range of techniques, including time-lapse and BIFC microscopy, we describe new molecular implications of the exomer complex in protein sorting and address its different layers of functional interaction with clathrin adaptor complexes. Exomer mutants show impaired amino acid uptake because it facilitates not only the polarized delivery of amino acid permeases to the PM but also participates in their endosomal traffic. We propose a model for exomer where it modulates the recruitment of TGN clathrin adaptors directly or indirectly through the Arf1 function. Moreover, we describe an in vivo competitive relationship between the exomer and AP-1 complexes for the model cargo Chs3. These results highlight a broad role for exomer in regulating protein sorting at the TGN that is complementary to its role as cargo adaptor and present a model to understand the complexity of TGN protein sorting.Ministerio de Economía, Industria y Competitividad, Gobierno de España (Ministeri d'Economia, Indústria i Competitivitat), Grant/Award Number: CICYT/FEDER BFU2017-84508-P; Consejería de Educación, Junta de Castilla y León (Ministry of Education, Government of Castile-Leon), Grant/Award Number: SA116G19; Ministerio de Economía, Industria y Competitividad, Gobierno de España (Ministeri d'Economia, Indústria i Competitivitat), Grant/Award Number: RTC-2017-6468-2-AR; Ministerio de Economía, Industria y Competitividad, Gobierno de España (Ministeri d'Economia, Indústria i Competitivitat), Grant/Award Number: BIO2016-77776-P; Foundation for the National Institutes of Health (FNIH), Grant/Award Number: R01 GM092741Anton-Plagaro, C.; Sánchez, N.; Valle, R.; Mulet, JM.; Duncan, MC.; Roncero, C. (2021). Exomer complex regulates protein traffic at the TGN through differential interactions with cargos and clathrin adaptor complexes. The FASEB Journal. 35(6):1-26. https://doi.org/10.1096/fj.202002610R12635

Neuropilin-1 is a host factor for SARS-CoV-2 infection

SARS-CoV-2, the causative agent of COVID-19, uses the viral Spike (S) protein for host cell attachment and entry. The host protease furin cleaves the full-length precursor S glycoprotein into two associated polypeptides: S1 and S2. Cleavage of S generates a polybasic Arg-Arg-Ala-Arg C-terminal sequence on S1, which conforms to a C-end rule (CendR) motif that binds to cell surface Neuropilin-1 (NRP1) and Neuropilin-2 (NRP2) receptors. Here, we used X-ray crystallography and biochemical approaches to show that the S1 CendR motif directly bound NRP1. Blocking this interaction using RNAi or selective inhibitors reduced SARS-CoV-2 entry and infectivity in cell culture. NRP1 thus serves as a host factor for SARS-CoV-2 infection and may potentially provide a therapeutic target for COVID-19