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Peptide-binding assays suggest that SARS-CoV-2 receptors engage the endocytosis and autophagy machinery. SARS-CoV-2: From entry to autophagy? SARS-CoV-2, the virus that causes COVID-19, enters cells through endocytosis upon binding to the cell surface receptor ACE2 and potentially others, including integrins. Using bioinformatics, Mészáros et al. predicted the presence of short amino acid sequences, called short linear motifs (SLiMs), in the cytoplasmic tails of ACE2 and various integrins that may engage the endocytic and autophagic machinery. Using affinity binding assays, Kliche et al. not only confirmed that many of these predicted SLiMs interacted with target peptides in various components of the endocytosis and autophagy machinery, but also found that these interactions were regulated by the phosphorylation of SLiM-adjacent amino acids. Together, these findings have identified a potential link between autophagy and integrin signaling and could lead to new ways to prevent viral infection. The spike protein of SARS-CoV-2 binds the angiotensin-converting enzyme 2 (ACE2) on the host cell surface and subsequently enters host cells through receptor-mediated endocytosis. Additional cell receptors may be directly or indirectly involved, including integrins. The cytoplasmic tails of ACE2 and integrins contain several predicted short linear motifs (SLiMs) that may facilitate internalization of the virus as well as its subsequent propagation through processes such as autophagy. Here, we measured the binding affinity of predicted interactions between SLiMs in the cytoplasmic tails of ACE2 and integrin β3 with proteins that mediate endocytic trafficking and autophagy. We validated that a class I PDZ-binding motif mediated binding of ACE2 to the scaffolding proteins SNX27, NHERF3, and SHANK, and that a binding site for the clathrin adaptor AP2 μ2 in ACE2 overlaps with a phospho-dependent binding site for the SH2 domains of Src family tyrosine kinases. Furthermore, we validated that an LC3-interacting region (LIR) in integrin β3 bound to the ATG8 domains of the autophagy receptors MAP1LC3 and GABARAP in a manner enhanced by LIR-adjacent phosphorylation. Our results provide molecular links between cell receptors and mediators of endocytosis and autophagy that may facilitate viral entry and propagation.

Cytoplasmic short linear motifs in ACE2 and integrin β 3 link SARS-CoV-2 host cell receptors to mediators of endocytosis and autophagy

Cytoplasmic short linear motifs in ACE2 and integrin β ₃ link SARS-CoV-2 host cell receptors to mediators of endocytosis and autophagy