ISG15-dependent activation of the sensor MDA5 is antagonized by the SARS-CoV-2 papain-like protease to evade host innate immunity

Invasion of RNA virus to cells is sensored by pattern-recognizing intracellular receptor such as RIG-I and MDA5 to induce antiviral state. ISG15 acts as a ubiquitin-like conjugation  that plays an essential role to adjust the signaling pathway. MDA5 signaling requires ISG15 conjugation, and in this report, it was demonstrated that SARS-CoV-2 nsp3, papain-like protease antagonizes ISG-15 dependent MDA5 activation via its de-ISGylaton activity.