Webster Brant M, Colombi Paolo, Jäger Jens, Lusk C Patrick
Department of Cell Biology, Yale School of Medicine, New Haven, CT 06520, USA.
Department of Cell Biology, Yale School of Medicine, New Haven, CT 06520, USA.
Cell. 2014 Oct 9;159(2):388-401. doi: 10.1016/j.cell.2014.09.012.
The maintenance of nuclear compartmentalization by the nuclear envelope and nuclear pore complexes (NPCs) is essential for cell function; loss of compartmentalization is associated with cancers, laminopathies, and aging. We uncovered a pathway that surveils NPC assembly intermediates to promote the formation of functional NPCs. Surveillance is mediated by Heh2, a member of the LEM (Lap2-emerin-MAN1) family of integral inner nuclear membrane proteins, which binds to an early NPC assembly intermediate, but not to mature NPCs. Heh2 recruits the endosomal sorting complex required for transport (ESCRT)-III subunit Snf7 and the AAA-ATPase Vps4 to destabilize and clear defective NPC assembly intermediates. When surveillance or clearance is compromised, malformed NPCs accumulate in a storage of improperly assembled nuclear pore complexes compartment, or SINC. The SINC is retained in old mothers to prevent loss of daughter lifespan, highlighting a continuum of mechanisms to ensure nuclear compartmentalization.
核膜和核孔复合体（NPC）维持核区室化对于细胞功能至关重要；区室化的丧失与癌症、核纤层蛋白病和衰老相关。我们发现了一条监测NPC组装中间体以促进功能性NPC形成的途径。监测由Heh2介导，Heh2是内核膜整合蛋白LEM（Lap2-emerin-MAN1）家族的成员，它与早期NPC组装中间体结合，但不与成熟NPC结合。Heh2招募运输所需的内体分选复合体（ESCRT）-III亚基Snf7和AAA-ATP酶Vps4，以破坏并清除有缺陷的NPC组装中间体。当监测或清除功能受损时，畸形的NPC会积聚在错误组装的核孔复合体储存区，即SINC中。SINC保留在衰老的母细胞中以防止子细胞寿命缩短，这突出了确保核区室化的一系列机制。
