Homotypic membrane fusion catalyzed by the atlastin (ATL) GTPase sustains the branched endoplasmic reticulum (ER) network in metazoans. Our recent discovery that two of the three human ATL paralogs (ATL1/2) are C-terminally autoinhibited implied that relief of autoinhibition would be integral to the ATL fusion mechanism. An alternative hypothesis is that the third paralog ATL3 promotes constitutive ER fusion with relief of ATL1/2 autoinhibition used conditionally. However, published studies suggest ATL3 is a weak fusogen at best. Contrary to expectations, we demonstrate here that purified human ATL3 catalyzes efficient membrane fusion in vitro and is sufficient to sustain the ER network in triple knockout cells. Strikingly, ATL3 lacks any detectable C-terminal autoinhibition, like the invertebrate Drosophila ATL ortholog. Phylogenetic analysis of ATL C-termini indicates that C-terminal autoinhibition is a recent evolutionary innovation. We suggest that ATL3 is a constitutive ER fusion catalyst and that ATL1/2 autoinhibition likely evolved in vertebrates as a means of upregulating ER fusion activity on demand.

中文翻译：

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人 atlastin-3 是一种组成型 ER 膜融合催化剂

由 atlastin (ATL) GTPase 催化的同型膜融合维持后生动物中的分支内质网 (ER) 网络。我们最近发现三个人类 ATL 旁系同源物 (ATL1/2) 中的两个是 C 端自抑制，这意味着自抑制的缓解将是 ATL 融合机制不可或缺的一部分。另一种假设是第三个旁系同源物 ATL3 促进 ER 组成型融合，并有条件地缓解 ATL1/2 自抑制。然而，已发表的研究表明 ATL3 充其量只是一种弱融合剂。与预期相反，我们在这里证明纯化的人 ATL3 在体外催化有效的膜融合，并且足以维持三重敲除细胞中的 ER 网络。引人注目的是，ATL3 缺乏任何可检测到的 C 端自抑制，就像无脊椎动物果蝇 ATL 直向同源物一样。 ATL C 末端的系统发育分析表明，C 末端自动抑制是最近的进化创新。我们认为 ATL3 是一种组成型 ER 融合催化剂，并且 ATL1/2 自抑制可能在脊椎动物中进化而来，作为按需上调 ER 融合活性的一种手段。