LAUSR

The ongoing pandemic of severe acute respiratory coronavirus 2 (SARS‐CoV‐2) is causing a devastating impact on public health worldwide. However, details concerning the profound impact of SARS‐CoV‐2 on host cells remain elusive. Here, we investigated the effects of SARS‐CoV‐2‐encoded viral proteins on the intracellular activity of long interspersed element 1 (L1) retrotransposons using well‐established reporter systems. Several nonstructural or accessory proteins (Nsps) of SARS‐CoV‐2 (i.e., Nsp1, Nsp3, Nsp5, and Nsp14) significantly suppress human L1 mobility, and these viral L1 inhibitors generate a complex network that modulates L1 transposition. Specifically, Nsp1 and Nsp14 inhibit the intracellular accumulation of L1 open reading frame proteins (ORF1p), whereas Nsp3, Nsp5, and Nsp14 repress the reverse transcriptase activity of L1 ORF2p. Given recent findings concerning the roles of L1 in antiviral immune activation and host genome instability, the anti‐L1 activities mediated by SARS‐CoV‐2‐encoded inhibitors suggest that SARS‐CoV‐2 employs different strategies to optimize the host genetic environment.