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1. Lipid and protein dynamics that shape nuclear envelope identity

   https://doi.org/10.1091/mbc.E18-10-0636  

   Bahmanyar, Shirin; Schlieker, Christian (June 2020, Molecular Biology of the Cell)

   Kozminski, Keith (Ed.)

   The nuclear envelope (NE) is continuous with the endoplasmic reticulum (ER), yet the NE carries out many functions distinct from those of bulk ER. This functional specialization depends on a unique protein composition that defines NE identity and must be both established and actively maintained. The NE undergoes extensive remodeling in interphase and mitosis, so mechanisms that seal NE holes and protect its unique composition are critical for maintaining its functions. New evidence shows that closure of NE holes relies on regulated de novo lipid synthesis, providing a link between lipid metabolism and generating and maintaining NE identity. Here, we review regulation of the lipid bilayers of the NE and suggest ways to generate lipid asymmetry across the NE despite its direct continuity with the ER. We also discuss the elusive mechanism of membrane fusion during nuclear pore complex (NPC) biogenesis. We propose a model in which NPC biogenesis is carefully controlled to ensure that a permeability barrier has been established before membrane fusion, thereby avoiding a major threat to compartmentalization. 

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

   https://doi.org/10.1101/2025.09.01.673543  

   Odell, Jacob; Nedza, Kristen; Lammerding, Jan (September 2025, bioRxiv)

   Abstract 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 emerin’s 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 emerin’s 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, thereby illuminating how diverse mutations in lamin A/C result in EDMD. 

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3. Towards understanding inner nuclear membrane protein degradation in plants

   https://doi.org/10.1093/jxb/erac037  

   Calvanese, Enrico; Gu, Yangnan; Spoel, ed., Steven (February 2022, Journal of Experimental Botany)

   Abstract The inner nuclear membrane (INM) hosts a unique set of membrane proteins that play essential roles in various aspects of the nuclear function. However, overaccumulation or malfunction of INM protein has been associated with a range of rare genetic diseases; therefore, maintaining the homeostasis and integrity of INM proteins by active removal of aberrantly accumulated proteins and replacing defective molecules through proteolysis is of critical importance. Within the last decade, it has been shown that INM proteins are degraded in yeasts by a process very similar to endoplasmic reticulum-associated degradation (ERAD), which is accomplished by retrotranslocation of membrane substrates followed by proteasome-dependent proteolysis, and this process was named inner nuclear membrane-associated degradation (INMAD). INMAD is distinguished from ERAD by specific INM-localized E3 ubiquitin ligases and proteolysis regulators. While much is yet to be determined about the INMAD pathway in yeasts, virtually no knowledge of it exists for higher eukaryotes, and only very recently have several critical regulators that participate in INM protein degradation been discovered in plants. Here, we review key molecular components of the INMAD pathway and draw parallels between the yeast and plant system to discuss promising directions in the future study of the plant INMAD process. 

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4. Structural insights into perilipin 3 membrane association in response to diacylglycerol accumulation

   https://doi.org/10.1038/s41467-023-38725-w  

   Choi, Yong Mi; Ajjaji, Dalila; Fleming, Kaelin D.; Borbat, Peter P.; Jenkins, Meredith L.; Moeller, Brandon E.; Fernando, Shaveen; Bhatia, Surita R.; Freed, Jack H.; Burke, John E.; et al (June 2023, Nature Communications)

   Abstract Lipid droplets (LDs) are dynamic organelles that contain an oil core mainly composed of triglycerides (TAG) that is surrounded by a phospholipid monolayer and LD-associated proteins called perilipins (PLINs). During LD biogenesis, perilipin 3 (PLIN3) is recruited to nascent LDs as they emerge from the endoplasmic reticulum. Here, we analyze how lipid composition affects PLIN3 recruitment to membrane bilayers and LDs, and the structural changes that occur upon membrane binding. We find that the TAG precursors phosphatidic acid and diacylglycerol (DAG) recruit PLIN3 to membrane bilayers and define an expanded Perilipin-ADRP-Tip47 (PAT) domain that preferentially binds DAG-enriched membranes. Membrane binding induces a disorder to order transition of alpha helices within the PAT domain and 11-mer repeats, with intramolecular distance measurements consistent with the expanded PAT domain adopting a folded but dynamic structure upon membrane binding. In cells, PLIN3 is recruited to DAG-enriched ER membranes, and this requires both the PAT domain and 11-mer repeats. This provides molecular details of PLIN3 recruitment to nascent LDs and identifies a function of the PAT domain of PLIN3 in DAG binding. 

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5. Differential reliance of CTD-nuclear envelope phosphatase 1 on its regulatory subunit in ER lipid synthesis and storage

   https://doi.org/10.1091/mbc.E23-09-0382  

   Carrasquillo_Rodríguez, Jake W; Uche, Onyedikachi; Gao, Shujuan; Lee, Shoken; Airola, Michael V; Bahmanyar, Shirin (July 2024, Molecular Biology of the Cell)

   Thibault, Guillaume (Ed.)

   Lipin 1 is an ER enzyme that produces diacylglycerol, the lipid intermediate that feeds into the synthesis of glycerophospholipids for membrane expansion or triacylglycerol for storage into lipid droplets. CTD-Nuclear Envelope Phosphatase 1 (CTDNEP1) regulates lipin 1 to restrict ER membrane synthesis, but a role for CTDNEP1 in lipid storage in mammalian cells is not known. Furthermore, how NEP1R1, the regulatory subunit of CTDNEP1, contributes to these functions in mammalian cells is not fully understood. Here, we show that CTDNEP1 is reliant on NEP1R1 for its stability and function in limiting ER expansion. CTDNEP1 contains an amphipathic helix at its N-terminus that targets to the ER, nuclear envelope and lipid droplets. We identify key residues at the binding interface of CTDNEP1 and NEP1R1 and show that they facilitate complex formation in vivo and in vitro. We demonstrate that NEP1R1 binding to CTDNEP1 shields CTDNEP1 from proteasomal degradation to regulate lipin 1 and restrict ER size. Unexpectedly, NEP1R1 was not required for CTDNEP1’s role in restricting lipid droplet biogenesis. Thus, the reliance of CTDNEP1 function on NEP1R1 depends on cellular demands for membrane production versus lipid storage. Together, our work provides a framework into understanding how the ER regulates lipid synthesis under different metabolic conditions. 

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