SARS-CoV-2 is the causative agent of the current COVID-19 pandemic. A major virulence factor of SARS-CoVs is the nonstructural protein 1 (Nsp1) which suppresses host gene expression by ribosome association. Here, we show that Nsp1 from SARS-CoV-2 binds to the 40S ribosomal subunit, resulting in shutdown of mRNA translation both in vitro and in cells. Structural analysis by cryo-electron microscopy (cryo-EM) of in vitro reconstituted Nsp1-40S and various native Nsp1-40S and -80S complexes revealed that the Nsp1 C terminus binds to and obstructs the mRNA entry tunnel. Thereby, Nsp1 effectively blocks RIG-I-dependent innate immune responses that would otherwise facilitate clearance of the infection. Thus, the structural characterization of the inhibitory mechanism of Nsp1 may aid structure-based drug design against SARS-CoV-2.

Initially, the pandemic COVID-19, caused by SARS-CoV-2, was considered to be an exclusive lung disease, eventually leading to serious respiratory symptoms 1 . In the meantime, accumulating experimental and clinical studies have suggested that SARS-CoV-2 may also cause lesions in the kidneys, heart, brain, and gastrointestinal and endocrine organs [2][3][4][5][6][7] . SARS-CoV-2 tropism towards distinct tissues is governed by cellular factors expressed on target cells such as the viral entry receptor angiotensin-converting enzyme 2 (ACE2) 8 and the transmembrane serine protease 2 (TMPRSS2) 8 . ACE2 messenger RNA 9-13 and protein 12-14 expression within the islets of Langerhans has been reported, but not yet been shown, to allow SARS-CoV-2 entry 9,12,15 . Diabetes mellitus presents Janus like in 16 ): first, pre-existing diabetes is a highly prevalent comorbidity observed in 11-22% of patients and as such increases the risk of a severe disease, requiring more intense interventions and increasing mortality [17][18][19][20][21][22] . Second, SARS-CoV-2 infection seems to affect the exocrine pancreas, manifesting as pancreatitis in 32.5% of critically ill patients 23 , and pancreatic enlargement and abnormal amylase or lipase levels in 7.5-17% of patients 9,22 . Third, metabolic dysregulation has been observed in patients with COVID-19 as:(1) increased hyperglycaemia in patients with type 2 diabetes 24 ; (2) ketoacidosis in 2-6.4% of diabetic and non-diabetic patients 18,25 ; and (3), in case studies reporting ketoacidosis on SARS-CoV-2 infection, accompanied by (4) new-onset type 1 diabetes mellitus (T1DM) in the absence of autoantibodies [26][27][28] . In a cohort study of patients with diabetes, hyperglycaemia was reported in more than 50% of all cases, and almost a third experienced diabetic ketoacidosis 29 . Finally, a multicentre study found an 80% increase of new-onset T1DM in children during the COVID-19 pandemic 30 . In accordance, a recent meta-analysis summarizes that severe SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas

Highlights d Numerous SARS-CoV-2 proteins synergize to suppress immune sensing and signaling d Nsp14 targets IFNAR1 for lysosomal degradation d ORF3a and ORF7a block autophagy by different mechanisms d Synergistic treatment with IFN-g and -l1 is highly effective against SARS-CoV-2

SARS-CoV-2 is the causative agent of the current COVID-19 pandemic. A major virulence factor of SARS-CoVs is the nonstructural protein 1 (Nsp1) which suppresses host gene expression by ribosome association via an unknown mechanism. Here, we show that Nsp1 from SARS-CoV-2 binds to 40S and 80S ribosomes, resulting in shutdown of capped mRNA translation both in vitro and in cells. Structural analysis by cryo-electron microscopy (cryo-EM) of in vitro reconstituted Nsp1-40S and of native human Nsp1-ribosome complexes revealed that the Nsp1 C-terminus binds to and obstructs the mRNA entry tunnel. Thereby, Nsp1 effectively blocks RIG-Idependent innate immune responses that would otherwise facilitate clearance of the infection. Thus, the structural characterization of the inhibitory mechanism of Nsp1 may aid structure-based drug design against SARS-CoV-2.Coronaviruses (CoVs) are enveloped, single-stranded viruses

Guanylate-binding protein (GBP) 5 is an interferon (IFN)-inducible cellular factor reducing HIV-1 infectivity by an incompletely understood mechanism. Here, we show that this activity is shared by GBP2, but not by other members of the human GBP family. GBP2/5 decrease the activity of the cellular proprotein convertase furin, which mediates conversion of the HIV-1 envelope protein (Env) precursor gp160 into mature gp120 and gp41. Because this process primes HIV-1 Env for membrane fusion, viral particles produced in the presence of GBP2/5 are poorly infectious due to increased incorporation of nonfunctional gp160. Furin activity is critical for the processing of envelope glycoproteins of many viral pathogens. Consistently, GBP2/5 also inhibit Zika, measles, and influenza A virus replication and decrease infectivity of viral particles carrying glycoproteins of Marburg and murine leukemia viruses. Collectively, our results show that GPB2/5 exert broad antiviral activity by suppressing the activity of the virus-dependency factor furin.