Discovery of Genes that Modulate Flavivirus Replication in an Interferon-Dependent Manner

Abstract

Establishment of the interferon (IFN)-mediated antiviral state provides a crucial initial line of defense against viral infection. Numerous genes that contribute to this antiviral state remain to be identified. Using a loss-of-function strategy, we screened an original library of 1156 siRNAs targeting 386 individual curated human genes in stimulated microglial cells infected with Zika virus (ZIKV), an emerging RNA virus that belongs to the flavivirus genus. The screen recovered twenty-one potential host proteins that modulate ZIKV replication in an IFN-dependent manner, including the previously known IFITM3 and LY6E. Further characterization contributed to delineate the spectrum of action of these genes towards other pathogenic RNA viruses, including Hepatitis C virus and SARS-CoV-2. Our data revealed that APOL3 acts as a proviral factor for ZIKV and several other related and unrelated RNA viruses. In addition, we showed that MTA2, a chromatin remodeling factor, possesses potent flavivirus-specific antiviral functions induced by IFN. Our work identified previously unrecognized genes that modulate the replication of RNA viruses in an IFN-dependent manner, opening new perspectives to target weakness points in the life cycle of these viruses.

Apolipoproteins L1 and L3 control mitochondrial membrane dynamics

“… 42 , 43 , 44 , 45 Interestingly, this proviral activity involves APOL3. 46 G1/G2 hit 2 could result from interference with virus-induced autophagy, as reducing autophagy particularly affects podocytes, 47 and autophagy is crucial to digest viral aggresomes. 48 Because G1/G2 expression causes dysfunction of both autophagy and mitochondrion activity, 49 , 50 , 51 the APOL1 variants may specifically perturb mitophagy, induced at mitochondrion-ER contact sites (MERCSs) to maintain mitochondrial function despite membrane damage due to the inflammatory reaction.…”

Intratumor APOL3 delineates a distinctive immunogenic ferroptosis subset with prognosis prediction in colorectal cancer

“…Based on the Zhongshan ferroptosis score 13 and integrated screen, we identified that tumor expressing APOL3 mediated enhanced ferroptosis sensitivity and CD8+ T cell antitumor ability 14 . Existing literature has elucidated the potential immunogenic role of APOL3 in innate immunity in cancer and noncancer models 15–17 . However, the prognostic and predictive value of APOL3 in CRC remains unclear.…”

“… 14 Existing literature has elucidated the potential immunogenic role of APOL3 in innate immunity in cancer and noncancer models. 15 , 16 , 17 However, the prognostic and predictive value of APOL3 in CRC remains unclear.…”