The Nemp1–Nesprin complex mediates cellular responses to matrix mechanics

This study identifies Nuclear Envelope Membrane Protein 1 (NEMP1) as a key nuclear-mechanotransduction component required for cell survival under mechanically stressful conditions. In vivo, the authors show that oocyte loss and infertility in Nemp1 knockout mice are driven by the stiff, collagen-rich ovarian cortex: reducing ovarian stiffness via Lox haploinsufficiency partially rescues primordial follicle survival and restores fertility. In vitro, NEMP1-depleted cells undergo apoptosis on stiff substrates but remain viable on soft substrates, demonstrating a stiffness-dependent survival requirement. Mechanistically, NEMP1 is required for mechanosensitive YAP nuclear localization: NEMP1 loss reduces YAP nuclear translocation on stiff matrices and after mechanical stretching, and constitutively nuclear YAP (YAP5SA) rescues cell viability. NEMP1 deficiency disrupts actin organization and lowers actin coherence; pharmacologic actin polymerization partially restores YAP nuclear localization, placing cytoskeletal integrity downstream of NEMP1 in this pathway. Finally, the authors demonstrate that NEMP1 forms a complex with the KASH domain of NESPRINs (e.g., NESPRIN2) independently of SUN1/2, defining a SUN-independent nuclear–cytoskeletal linkage (“Nemp1–Nesprin complex”) that operates in parallel to the canonical LINC complex to support actin-dependent mechanotransduction and cell survival on stiff environments.