Impaired RNA metabolism has been implicated in amyotrophic lateral sclerosis (ALS). Xu et al. report that the nonsense-mediated mRNA decay (NMD) pathway is inhibited in C9orf72 hexanucleotide repeat expansion-associated ALS. Reactivation of the NMD pathway protects against neurodegeneration in ALS models, suggesting potential as a therapeutic strategy.

Valosin-containing protein/p97(VCP) is a hexameric ATPase vital to protein degradation during endoplasmic reticulum stress. It regulates diverse cellular functions including autophagy, chromatin remodeling, and DNA repair. In addition, mutations in VCP cause inclusion body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD), as well as amyotrophic lateral sclerosis. Nevertheless, how the VCP activities were regulated and how the pathogenic mutations affect the function of VCP during stress are not unclear. Here we show that the small ubiquitin-like modifier (SUMO)-ylation of VCP is a normal stress response inhibited by the disease-causing mutations in the N-domain. Under oxidative and endoplasmic reticulum stress conditions, the SUMOylation of VCP facilitates the distribution of VCP to stress granules and nucleus, and promotes the VCP hexamer assembly. In contrast, pathogenic mutations in the VCP N-domain lead to reduced SUMOylation and weakened VCP hexamer formation upon stress. Defective SUMOylation of VCP also causes altered co-factor binding and attenuated endoplasmic reticulum-associated protein degradation. Furthermore, SUMO-defective VCP fails to protect against stress-induced toxicity in Drosophila. Therefore, our results have revealed SUMOylation as a molecular signaling switch to regulate the distribution and functions of VCP during stress response, and suggest that deficiency in VCP SUMOylation caused by pathogenic mutations will render cells vulnerable to stress insults.Valosin-containing protein (VCP/p97, cdc48, 2 is a highly conserved member of AAA (ATPase associated with diverse cellular activities) family proteins. It is mainly composed of N-domain and two ATPase domains. By forming a homohexamer and binding various co-factors via the N-domain, VCP helps to remodel, unfold, or degrade protein substrates using the energy derived from ATP hydrolysis (1-3). Due to its cellular abundance and broad interaction with a number of co-factors, key substrates, and regulators of the ubiquitin proteasome system, VCP has emerged as a vital modulator of a large variety of cellular activities, including protein degradation, ER stress response, autophagy/mitophagy, endosomal trafficking, cell cycle, and DNA repair (2, 5, 6). However, the factors that regulate VCP activities are not clear.The importance of VCP is also demonstrated by its association with cancer and degenerative diseases. VCP is highly expressed in non-small cell lung carcinoma (7), and its expression is correlated with tumor progression and prognosis (8). On the other hand, mutations in VCP have been associated with degenerative diseases, including inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) and amyotrophic lateral sclerosis (ALS) (6, 9). Most pathogenic mutations of VCP are found in the N-domain, with a few in the ATPase domains (10). The pathology of VCP-associated degenerative diseases features ubiquitin-positive inclusions. Although some of the pathogenic VCP mutation...