Jcb_201410047 1..11

Nuclear pore complexes (NPCs) are multiprotein transport channels that span the nuclear envelope (NE) and serve as exclusive communication conduits between the nucleus and the cytoplasm (Hoelz et al., 2011). NPCs are composed of multiple copies of 30 different proteins called nucleoporins or Nups (Allen et al., 2001; Cronshaw et al., 2002). Although the primary function of NPCs has been traditionally viewed to be nucleocytoplasmic transport, recent studies in eukaryotes ranging from yeast to mammals indicate that nucleoporins play roles in nuclear processes such as chromatin organization and gene regulation (Akhtar and Gasser, 2007; Brown and Silver, 2007; Liang and Hetzer, 2011). Moreover, accumulating evidence suggests that NPCs have cell type–specific composition (Raices and D’Angelo, 2012; Ori et al., 2013) and that single nucleoporin mutations often give rise to developmental defects and human diseases (Nakamura et al., 1996; Zhang et al., 2008; Lupu et al., 2008; Gomez-Cavazos and Hetzer, 2012). Altogether, these studies raise the exciting possibility that a subset of nucleoporins might act as critical regulators of gene expression programs during differentiation and development in a transportindependent manner. One striking example of a NPC protein that exhibits cell type–specific expression is the transmembrane nucleoporin gp210/Nup210 (herein referred to as Nup210). Nup210 was the first nucleoporin to be discovered more than three decades ago, and as a result of its membrane association and close resemblance to viral fusogenic proteins, it was initially predicted to promote the fusion between the inner nuclear membrane and outer nuclear membrane during NPC biogenesis (Gerace et al., 1982; Wozniak et al., 1989). However, several studies have shown that Nup210 is absent in many tissue types and found to be dispensable for NPC assembly, maintenance, and distribution (Olsson et al., 1999, 2004; Eriksson et al., 2004; Stavru et al., 2006; Ori et al., 2013). This raises the important question Previously, we identified the nucleoporin gp210/ Nup210 as a critical regulator of muscle and neuronal differentiation, but how this nucleoporin exerts its function and whether it modulates nuclear pore complex (NPC) activity remain unknown. Here, we show that gp210/Nup210 mediates muscle cell differentiation in vitro via its conserved N-terminal domain that extends into the perinuclear space. Removal of the C-terminal domain, which partially mislocalizes gp210/Nup210 away from NPCs, efficiently rescues the differentiation defect caused by the knockdown of endogenous gp210/ Nup210. Unexpectedly, a gp210/Nup210 mutant lacking the NPC-targeting transmembrane and C-terminal domains is sufficient for C2C12 myoblast differentiation. We demonstrate that the endoplasmic reticulum (ER) stressspecific caspase cascade is exacerbated during Nup210 depletion and that blocking ER stress-mediated apoptosis rescues differentiation of Nup210-deficient cells. Our results suggest that the role of gp210/Nup210 in cell differentiation is mediated by its large luminal domain, which can act independently of NPC association and appears to play a pivotal role in the maintenance of nuclear envelope/ER homeostasis. The nucleoporin gp210/Nup210 controls muscle differentiation by regulating nuclear envelope/ER homeostasis