New Roles of bZIP-Containing Membrane-Bound Transcription Factors in Chromatin Tethering and Karyoptosis

The nuclear membrane has emerged as a dynamic regulatory platform coordinating genome organization, mechanotransduction, and regulated cell death (RCD). Beyond its barrier function, the nuclear skeleton—comprising lamins, actin–myosin isoforms, nuclear matrix proteins, and the LINC complex—supports nuclear integrity and gene regulation. Recent evidence shows that type II membrane-bound bZIP transcription factors such as cAMP-responsive element-binding protein 3 (CREB3) and CREB3L1 localize to the inner nuclear membrane (INM), linking chromatin tethering with stress signaling. Their stress-induced cleavage by S1P/S2P disrupts chromatin anchoring and, in some contexts, triggers karyoptosis, a novel form of RCD defined by nuclear rupture. These findings position the nuclear envelope (NE) as a mechanosensitive signaling hub with direct implications for disease and therapy. In this review, we provide a comprehensive discussion on how type II membrane-bound bZIP transcription factors and chromatin acting as a nucleoskeleton cooperate to regulate nuclear membrane integrity.