LRRC59 modulates type I interferon signaling by restraining the SQSTM1/p62-mediated autophagic degradation of pattern recognition receptor DDX58/RIG-I
Authors: Huifang Xian
Yuxia Zhang
Jun Cui
Shuai Yang
Shouheng Jin
Journal: Autophagy (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Autophagic degradation; DDX58/RIG-I; LRRC59; cargo receptor; type I interferon.
Affiliations: Department of Internal Medicine, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, and MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, GD, China, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, GD, China

Abstract:  DDX58/RIG-I, is a critical pattern recognition receptor for viral RNA, which plays an essential role in antiviral immunity. Its posttranslational modifications and stability are tightly regulated to mediate the moderate production of type I IFN to maintain the immune homeostasis. Recently, we reported that macroautophagy/autophagy balances type I IFN signaling through selective degradation of ISG15-associated DDX58 via LRRC25. However, the regulatory mechanism about the autophagic degradation of DDX58 remains largely undefined. Here, we identified LRRC59 as a vital positive regulator of DDX58-mediated type I IFN signaling. Upon virus infection, LRRC59 specifically interacted with ISG15-associated DDX58 and blocked its association with LRRC25, the secondary receptor to deliver DDX58 to autophagosomes for SQSTM1/p62-dependent degradation, leading to the stronger antiviral immune responses. Thus, our study reveals a novel regulatory role of selective autophagy in innate antiviral responses mediated by the cross-regulation of LRRC family members. These data further provide insights into the crosstalk between autophagy and innate immune responses.Abbreviations: ATG: Autophagy-related; Baf A1: Bafilomycin A1; DDX58/RIG-I: DEAD [Asp-Glu-Ala-Asp] box polypeptide 58; EV: Empty vector; IC poly[I:C]: Intracellular polyriboinosinic polyribocytidylic acid; IFIH1/MDA5: Interferon induced with helicase C domain 1; IFN: Interferon; ISG15: ISG15 ubiquitin like modifier; IKBKE: Inhibitor of nuclear factor kappa B kinase subunit epsilon; IRF3: Interferon regulatory factor 3; KO: Knockout; LRRC: Leucine rich repeat containing; MAVS: Mitochondrial antiviral signaling protein; CGAS/MB21D1: Cyclic GMP-AMP synthase; SeV: Sendai virus; siRNA: small interfering RNA; SQSTM1/p62: Sequestosome 1; TBK1: TANK binding kinase 1; TLR: Toll like receptor; TMEM173/STING: Transmembrane protein 173; VSV: Vesicular stomatitis virus; WT: Wild type. 

Retracted: No

PubPeer comments:
 In Figure 4d,f, many of the Western blots contain areas which are empty, where no signal is detected when adjusting the contrast. ![file] , 
 Thanks for raising this concern. Since the signal is strong, and the background is low, the merge of the image might lose some resolution. We provided our original data here. Best regards Huifang Xian 4d-IP-Myc, ![file] 4d-WCL-Myc, ![file] 4d-WCL-Flag, ![file] 4f-IP-GFP, ![file] 4f-WCL-HA, ![file] , 
 It s interesting to see that you now, by some magical way, are able to get a background on your western immunoblots The blots you presented do not look like the ones presented in your published paper. Many of the bands are different, as for the background. ![file] ,