Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.
Department of Cell Biology, Harvard Medical School, Boston, MA.
J Cell Biol. 2020 Jun 1;219(6). doi: 10.1083/jcb.201908232.
The nuclear envelope (NE) undergoes dynamic remodeling to maintain NE integrity, a process involving the inner nuclear membrane protein LEM2 recruiting CHMP7/Cmp7 and then ESCRT-III. However, prior work has hinted at CHMP7/ESCRT-independent mechanisms. To identify such mechanisms, we studied NE assembly in Schizosaccharomyces japonicus, a fission yeast that undergoes partial mitotic NE breakdown and reassembly. S. japonicus cells lacking Cmp7 have compromised NE sealing after mitosis but are viable. A genetic screen identified mutations that promote NE integrity in cmp7Δ cells. Unexpectedly, loss of Lem2 or its interacting partner Nur1 suppressed cmp7Δ defects. In the absence of Cmp7, Lem2 formed aggregates that appear to interfere with ESCRT-independent NE sealing. A gain-of-function mutation implicated a membrane and ESCRT-III regulator, Alx1, in this alternate pathway. Additional results suggest a potentially general role for unsaturated fatty acids in NE integrity. These findings establish the existence of mechanisms for NE sealing independent of the canonical ESCRT pathway.
核膜（NE）经历动态重塑以维持 NE 完整性，这一过程涉及内核膜蛋白 LEM2 招募 CHMP7/Cmp7，然后招募 ESCRT-III。然而，先前的工作表明存在 CHMP7/ESCRT 独立的机制。为了确定这些机制，我们研究了裂殖酵母 Schizosaccharomyces japonicus 中的 NE 组装，裂殖酵母在有丝分裂过程中经历部分核膜破裂和重组装。缺乏 Cmp7 的 S. japonicus 细胞在有丝分裂后 NE 密封受损，但仍具有活力。遗传筛选鉴定出促进 cmp7Δ 细胞 NE 完整性的突变。出乎意料的是，Lem2 或其相互作用伙伴 Nur1 的缺失抑制了 cmp7Δ 缺陷。在没有 Cmp7 的情况下，Lem2 形成聚集体，似乎干扰了非 ESCRT 依赖的 NE 密封。功能获得性突变将膜和 ESCRT-III 调节剂 Alx1 牵连到这个替代途径中。其他结果表明不饱和脂肪酸在 NE 完整性中可能具有普遍作用。这些发现确立了独立于经典 ESCRT 途径的 NE 密封机制的存在。
