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<p>Double-stranded RNA (dsRNA) binding proteins (dsRBPs) play crucial roles in various cellular processes, especially in the innate immune response. Comprehensive characterization of dsRBPs is essential to understand the intricate mechanisms for dsRNA sensing and response. Traditional methods have predominantly relied on affinity purification, favoring the isolation of strong dsRNA binders. Here, we adopt the proteome integral solubility alteration (PISA) workflow for characterizing dsRBPs, resulting in the observation of 18 known dsRBPs and the identification of 200 potential dsRBPs. Next, we focus on zinc finger protein 385 A (ZNF385A) and discover that its knockout activates the transcription of interferon-β in the absence of immunogenic stimuli. The knockout of ZNF385A elevates the level of endogenous dsRNAs, especially transcripts associated with retroelements, such as short interspersed nuclear element (SINE), long interspersed nuclear element (LINE), and long terminal repeat (LTR). Moreover, loss of ZNF385A enhances the bioactivity of 5-Aza-2’-deoxycytidine (5-AZA-CdR) and tumor-killing effect of NK cells. Our findings greatly expand the dsRBP reservoir and contribute to the understanding of cellular dsRNA homeostasis.</p>

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Characterization of dsRNA binding proteins through solubility analysis identifies ZNF385A as a dsRNA homeostasis regulator

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月11日

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  • Na Jiang,
  • Hekun Yang,
  • Yi Lei,
  • Weida Qin,
  • Huifang Xiong,
  • Kuan Chen,
  • Kunrong Mei,
  • Gongyu Li,
  • Xin Mu,
  • Ruibing Chen

摘要

Double-stranded RNA (dsRNA) binding proteins (dsRBPs) play crucial roles in various cellular processes, especially in the innate immune response. Comprehensive characterization of dsRBPs is essential to understand the intricate mechanisms for dsRNA sensing and response. Traditional methods have predominantly relied on affinity purification, favoring the isolation of strong dsRNA binders. Here, we adopt the proteome integral solubility alteration (PISA) workflow for characterizing dsRBPs, resulting in the observation of 18 known dsRBPs and the identification of 200 potential dsRBPs. Next, we focus on zinc finger protein 385 A (ZNF385A) and discover that its knockout activates the transcription of interferon-β in the absence of immunogenic stimuli. The knockout of ZNF385A elevates the level of endogenous dsRNAs, especially transcripts associated with retroelements, such as short interspersed nuclear element (SINE), long interspersed nuclear element (LINE), and long terminal repeat (LTR). Moreover, loss of ZNF385A enhances the bioactivity of 5-Aza-2’-deoxycytidine (5-AZA-CdR) and tumor-killing effect of NK cells. Our findings greatly expand the dsRBP reservoir and contribute to the understanding of cellular dsRNA homeostasis.