Liquid-liquid phase separation of ATXN2L enhances mRNA translation in hepatocellular carcinoma

Abstract

<p>RNA-binding proteins (RBPs) serve as key regulators of hepatocellular carcinoma (HCC); however, the specific mechanisms by which RBPs function in this context require clarification. Here, we identify an RBP, <em>ATXN2L</em> (ataxin 2-like), that is significantly upregulated in HCC tissues and correlates with a poor prognosis. Knockdown of <em>ATXN2L</em> in HCC cells or knockout of <em>Atxn2l</em> in mice suppresses HCC progression. Mechanistically, enhanced liquid-liquid phase separation (LLPS) activity of ATXN2L results in the formation of larger ATXN2L-positive granules, which facilitate the recruitment of several eukaryotic initiation factors (eIFs) and their downstream targets, such as <em>ADAM9</em> (ADAM metallopeptidase domain 9), thereby promoting mRNA translation. Moreover, the promotion of ATXN2L granules on <em>ADAM9</em> translation is further enhanced via co-localization with stress granules (SGs). Together, our findings reveal that ATXN2L functions as a critical translational regulator in HCC progression through LLPS activity, which could serve as an effective therapeutic target for HCC treatment.<br></p>