Metazoan stringent-like response mediated by MESH1 phenotypic conservation via distinct mechanisms.

All organisms are constantly exposed to various stresses, necessitating adaptive strategies for survival. In bacteria, the main metabolic stress-coping mechanism is the stringent response, which is triggered by the accumulation of "alarmone" (p)ppGpp to arrest proliferation and reprogram the transcriptome. The level of (p)ppGpp is regulated by its synthetase RelA and its hydrolase SpoT. MESH1 is the metazoan homolog of bacterial SpoT that regulates the bacterial stringent response by degrading the alarmone (p)ppGpp. While MESH1, like SpoT, can also dephosphorylate (p)ppGpp, mammalian cells do not have significant levels of this metabolite, and the relevant enzymatic activities and function of MESH1 have remained a mystery. Through genetic and biochemical analyses, we have solved the long-held mystery and identified MESH1 as the first mammalian cytosolic NADPH phosphatase involved in ferroptosis. Furthermore, we discovered that MESH1 removal leads to proliferation arrest, translation inhibition, and a prominent transcriptional and metabolic response. Therefore, MESH1 knockdown triggers a novel stress response with phenotypic conservation with the bacterial stringent response via distinct substrates and molecular pathways. Here, we summarize the background of the MESH1, illustrate the striking conservation of phenotypes in different organisms during evolution and discuss remaining questions in the field.

Zinc transporter ZIP7 is a novel determinant of ferroptosis.

Ferroptosis is a newly described form of regulated cell death triggered by oxidative stresses and characterized by extensive lipid peroxidation and membrane damages. The name of ferroptosis indicates that the ferroptotic death process depends on iron, but not other metals, as one of its canonical features. Here, we reported that zinc is also essential for ferroptosis in breast and renal cancer cells. Zinc chelator suppressed ferroptosis, and zinc addition promoted ferroptosis, even during iron chelation. By interrogating zinc-related genes in a genome-wide RNAi screen of ferroptosis, we identified SLC39A7, encoding ZIP7 that controls zinc transport from endoplasmic reticulum (ER) to cytosol, as a novel genetic determinant of ferroptosis. Genetic and chemical inhibition of the ZIP7 protected cells against ferroptosis, and the ferroptosis protection upon ZIP7 knockdown can be abolished by zinc supplementation. We found that the genetic and chemical inhibition of ZIP7 triggered ER stresses, including the induction of the expression of HERPUD1 and ATF3. Importantly, the knockdown of HERPUD1 abolished the ferroptosis protection phenotypes of ZIP7 inhibition. Together, we have uncovered an unexpected role of ZIP7 in ferroptosis by maintaining ER homeostasis. These findings may have therapeutic implications for human diseases involving ferroptosis and zinc dysregulations.

C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation.

Hexanucleotide repeat expansion in C9ORF72 is the most frequent cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we demonstrate that the repeat-associated non-AUG (RAN) translation of (GGGGCC) n -containing RNAs into poly-dipeptides can initiate in vivo without a 5'-cap. The primary RNA substrate for RAN translation of C9ORF72 sense repeats is shown to be the spliced first intron, following its excision from the initial pre-mRNA and transport to the cytoplasm. Cap-independent RAN translation is shown to be upregulated by various stress stimuli through phosphorylation of the α subunit of eukaryotic initiation factor-2 (eIF2α), the core event of an integrated stress response (ISR). Compounds inhibiting phospho-eIF2α-signaling pathways are shown to suppress RAN translation. Since the poly-dipeptides can themselves induce stress, these findings support a feedforward loop with initial repeat-mediated toxicity enhancing RAN translation and subsequent production of additional poly-dipeptides through ISR, thereby promoting progressive disease.