Nedza, K. | bioRxiv Science

bioRxiv2026

Antagonistic contributions of A-type and B-type lamins to LBR localization and dynamics

Lamin B receptor (LBR) is an inner nuclear membrane (INM) protein that plays crucial roles in maintaining nuclear architecture and organization of peripheral heterochromatin. Lamins and LBR both contribute to chromatin tethering at the nuclear periphery, and the expression of LBR and A-type lamins is tightly regulated during development to ensure a faithful transition between different chromatin tethering modalities. Despite its well-established association with B-type lamins, the contributions of individual lamin isoforms to LBR localization and anchorage have not been systematically examined. Here, we used mouse embryonic fibroblasts (MEFs) lacking all endogenous lamins (triple lamin knockout: TKO) to assess how specific lamin isoforms and domains regulate LBR subcellular localization and mobility. Whereas ectopic expression of either lamin B1 or lamin B2 was sufficient to tether LBR to the nuclear envelope in TKO cells, expression of lamin A increased the lateral mobility of LBR at the nuclear membrane, resulting in its displacement from the nuclear envelope to the ER. The lamin A-induced displacement of LBR was mediated by phosphorylation of LBR. Overexpression of lamin A in wild-type MEFs similarly increased LBR phosphorylation and promoted its displacement from the nuclear envelope. Collectively, these findings define isoform-specific and antagonistic roles for A-type and B-type lamins in regulating LBR anchorage at the nuclear envelope. In addition, they indicate a lamin A-dependent mechanism that may reflect a broader developmental process, since LBR and lamin A sequentially tether peripheral heterochromatin during development.

cell biology↗

bioRxiv2025

A-type lamins anchor emerin at the inner nuclear membrane via two independent binding sites

Lamins form a dense meshwork at the inner surface of the inner nuclear membrane (INM), where they interact with other nuclear envelope proteins such as emerin. Emerin is an integral membrane protein that is part of the LEM (LAP2/emerin/MAN1) domain family, and mutations in either emerin or lamin A/C can result in Emery-Dreifuss muscular dystrophy (EDMD) and other striated muscle diseases. Emerin is retained at the INM through direct interaction with lamin A/C, and emerins proper subcellular localization is critical for its ability to influence the mechanical properties of the nucleus and participate in various signaling processes. Nonetheless, the requirements for interaction between emerin and lamin A/C at the INM remain incompletely understood. Here, we report that two distinct regions of lamin A/C are each sufficient to properly localize emerin to the INM and prevent emerins lateral diffusion within the INM. In addition to a previously described region of the lamin A/C tail domain able to bind emerin, we identify a novel emerin-interacting domain comprising the linker between the rod and Ig-like fold domains of lamin A/C. We further demonstrate that stably anchoring emerin to the INM requires assembly of A-type lamins into a filamentous network. Collectively, our findings suggest a revised model for emerin retention at the INM, which predicts that two independent lamin A/C domains are required to retain emerin at the nuclear envelope.

cell biology↗