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SARS-CoV-2 poses a substantial global threat owing to the emergence of several highly transmissible variants. Autophagy is an intracellular degradation process that maintains cellular homeostasis and combats the invading pathogens. SARS-CoV-2 can trigger autophagy and antagonize interferon production. However, the underlying mechanisms remain elusive, particularly for different variants. Here, we found that SARS-CoV-2 nonstructural protein (NSP) 6 inhibited interferon production by promoting macroautophagy/autophagy-mediated STING1 degradation. Mechanistically, NSP6 induced endoplasmic reticulum stress and bound to HSPA5/GRP78, leading to the activation of EIF2AK3/PERK-EIF2A/EIf2α pathway-mediated autophagy, which was associated with lysosomal degradation of STING1 and downregulation of interferon production. Moreover, the 81–120 amino acid (aa) region of NSP6 is critical for autophagy induction and STING1 degradation. Interestingly, NSP6 harboring a three aa deletion in the 81–120 aa region of some SARS-CoV-2 variants led to reduced autophagy, STING1 degradation, and increased host antiviral immunity. Collectively, this study demonstrated a major function of NSP6 in the SARS-CoV-2 evasion of host antiviral immunity by triggering endoplasmic reticulum stress-induced autophagy to degrade STING1 and that enhancement of host antiviral immunity induced by NSP6 variants with a three-aa deletion might be responsible for the attenuation of SARS-CoV-2 variants. aa: amino acid; ATF6: activating transcription factor 6; ATG5: autophagy related 5; CCPG1: cell cycle progression 1; CFTR: CF transmembrane conductance regulator; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; CHX: cycloheximide; Co-IP: co-immunoprecipitation; CQ: chloroquine; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; GFP: green fluorescent protein; HSPA5/GRP78: heat shock protein family A (Hsp70) member 5; HSV-1: herpes simplex virus type 1; IFIT1: interferon induced protein with tetratricopeptide repeats 1; IFNB1/IFN-β: interferon beta 1; IRF3: interferon regulatory factor 3; ISG15: ISG15 ubiquitin like modifier; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MAVS: mitochondrial antiviral signaling protein; MOI: multiplicity of infection; NFKB/NF-κB: nuclear factor kappa B; NSP6: non-structural protein 6; Δ106–108: deletion of amino acids 106–108 in NSP6 of SARS-CoV-2; Δ105–107: deletion of amino acids 105–107 in NSP6 of SARS-CoV-2; RETREG1/FAM134B: reticulophagy regulator 1; RIGI/DDX58: RNA sensor RIG-I; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1. [ABSTRACT FROM AUTHOR]