iRhom2 is essential for innate immunity to RNA virus by antagonizing ER- and mitochondria-associated degradation of VISA
Authors: Chen Li
Pan Cao
Zhou-Qin Zheng
Su-Yun Wang
Wei-Wei Luo
Zhen Tong
Shu Li
Yan-Yi Wang
Huan Lian
Hong-Bing Shu
Journal: PLoS Pathogens (2017)
Discipline: MICROBIOLOGY
Keywords: VISA; innate immune response; RNA virus; iRhom2; E3 ubiquitin ligases
Affiliations: Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China., Medical Research Institute, State Key Laboratory of Virology, School of Medicine, Wuhan University, Wuhan, China., College of Life Sciences, Wuhan University, Wuhan, China.

Abstract:  VISA (also known as MAVS, IPS-1 and Cardif) is an essential adaptor protein in innate immune response to RNA virus. The protein level of VISA is delicately regulated before and after viral infection to ensure the optimal activation and timely termination of innate antiviral response. It has been reported that several E3 ubiquitin ligases can mediate the degradation of VISA, but how the stability of VISA is maintained before and after viral infection remains enigmatic. In this study, we found that the ER-associated inactive rhomboid protein 2 (iRhom2) plays an essential role in mounting an efficient innate immune response to RNA virus by maintaining the stability of VISA through distinct mechanisms. In un-infected and early infected cells, iRhom2 mediates auto-ubiquitination and degradation of the E3 ubiquitin ligase RNF5 and impairs the assembly of VISA-RNF5-GP78 complexes, thereby antagonizes ER-associated degradation (ERAD) of VISA. In the late phase of viral infection, iRhom2 mediates proteasome-dependent degradation of the E3 ubiquitin ligase MARCH5 and impairs mitochondria-associated degradation (MAD) of VISA. Maintenance of VISA stability by iRhom2 ensures efficient innate antiviral response at the early phase of viral infection and ready for next round of response. Our findings suggest that iRhom2 acts as a checkpoint for the ERAD/MAD of VISA, which ensures proper innate immune response to RNA virus. 

Retracted: No

PubPeer comments:
 Are the authors convinced of the relevance of all the references?  The researches in the past decades have indicated that the atherosclerotic cardiovascular disease is usually caused by complex interactions of the cellular mechanisms, for instance chronic inflammatory environment and intercellular interactions among endothelial cells, macrophages and smooth muscle cells, promote the progress and development of plaques.[1, 2] - [2]. Su, J.; Sheng, Z.; Leung, V. C. M.; Chen, Y. **Energy Efficient Tag Identification Algorithms for RFID: Survey, Motivation and New Design**. IEEE Wireless Commun. 2019, 26, 118u2013124. DOI: 10.1109 MWC.2019.1800249.  MicroRNAs (miRNAs) are drawing the attention of most researchers because of the important posttranscriptional regulators of a series of molecular signaling pathways, and miRNA-9 was reported taking important part in the atherosclerotic cardiovascular disease.[3] - [3]. Zhao, J.; Xin, M.; Zhang, J.; Sun, Y.; Luo, S.; Wang, H.; Wang, Y.; Bi, X. **Diclofenac Inhibited the Biological Phosphorus Removal: Performance and Mechanism**. Chemosphere 2020, 243, 125380. DOI: 10.1016 j.chemosphere.2019.125380.  The structure and design of novel coordination polymers (CPs) have attracted great attention owing to their fascinating topologies and structures, at the same time due to their attractive performances and latent applications in the fields of catalysis, magnetism and optics, adsorption as well as electrochemistry, and so on.[4u20137] - [7]. Liu, D.; Ding, C.; Chi, F.; Pan, N.; Wen, J.; Xiong, J.; Hu, S. **Polymer Brushes on Graphene Oxide for Efficient Adsorption of Heavy Metal Ions from Water**. J. Appl. Polym. Sci. 2019, 136, 48156. DOI: 10.1002 app.48156.  The flexible ligands of bis(pyridyl-tetrazole) have following merits: the first one, they include groups of 2 tetrozole along with 2 pyridyls, they can offer several coordination sites as well as display multiple coordination patterns; the second one, they include flexible backbones -(CH2)n-, which can rotate unrestricted to meet coordination requirement surroundings round the metal ions.[12u201315] - [13]. Chi, F.; Liu, D.; Wu, H.; Lei, J. **Mechanically Robust and Self-Cleaning Antireflection Coatings from Nanoscale Binding of Hydrophobic Silica Nanoparticles**. Sol. Energy Mater. Sol. C 2019, 200, 109939. DOI:10.1016 j.solmat.2019.109939. , 
 *[left]* Fig 3  The FT-IR spectra for the complexes 1 (c) . *[right]* Fig 2(b) from  Co(II) coordination polymer: crystal structure and treatment activity against chronic obstructive pulmonary disease ([Hu et al 2021] ),  The FT-IR spectrum of complex 1 . ![file] , 
 Another sighting! Fig 3  The FT-IR spectra for the complexes 1 (c) and 2 (d) . ![file] Fig 3 from  Two Co(II) coordination polymers: treatment and nursing values on acute renal failure during pregnancy by regulating the expression of aquaporin ([Hu et al 2021] ),  The FT-IR spectra for complexes 1 (c) and 2 (d) . ![file] UPDATE: Figure S1 from  (II) coordination polymer:application values on vulvovaginal candidiasis through reducing Candidauffffalbicans growth ([Wang, Song Jiang 2021] ),  The FT-IR spectrum of complex 1. ![file] But wait, there s more! Fig S1 from  Synthesis, structures and anti-diabetes activity of cobalt(II) coordination compounds ([Yang et al 2021] ),  The IR spectra of complexes 1 and 2. ![file] , 
 Another sighting! This appearance of the versatile FTIR is in  Indian Journal of Chemistry A , which is sponsored by  Council of Scientific Industrial Research; Indian National Science Academy; National Institute of Science Communication and Information Resources ... but the papers do not have DOIs, so no separate Pubpeer threads. Anyway, [Supplementary Figure S1](http: nopr.niscair.res.in bitstream 123456789 58616 2 IJCA-60A%2812%29%201551-1556_Suppl%20Data.pdf) from  New Mn(II)-coordination polymer based on flexible benzimidazol ligand: Crystal structure and application on osteosarcoma ([Ni et al 2021](http: nopr.niscair.res.in bitstream 123456789 58616 1 IJCA-60A%20%2812%29%201551-1556.pdf)),  Infrared spectrum of compound 1 . ![file] I wonder if the high reuse of Figures is a result of the crystallography papermill scaling up production. ,