A NUCLEAR PORE "FACTORY" DISCOVERED WITHIN OUR CELLS
How do cells build the thousands of pores that mediate exchanges between the nucleus and the cytoplasm?
In a paper published in Nature Communications, scientists reveal the unsuspected role of annulate lamellae as bona fide nuclear pore pre-assembly sites. This third pathway of pore formation contributes to nuclear growth, and its dysregulation may be implicated in certain pathologies.
The nucleus of cells is surrounded by a double membrane, the nuclear envelope, which separates the genetic material from the cytoplasm. This envelope is perforated by thousands of nuclear pores, gigantic protein assemblies that control exchanges between these two compartments. RNA, proteins, and signaling molecules must thus cross these veritable molecular gateways to enter or exit the nucleus.
Building and maintaining several thousand of these nuclear pore complexes over the course of cell growth and division represents a considerable challenge. Two pathways enabling their assembly had, until now, been well described in mammals. A study now reveals the existence of a third pathway, one that relies on cellular structures that have long remained enigmatic: annulate lamellae, or AL.
Nuclear pores assembled in advance
Annulate lamellae are membrane stacks located in the cytoplasm that contain structures strongly resembling nuclear pores. They have long been considered relatively static structures, or even mere storage sites for the proteins that make up these pores, the nucleoporins.
The scientists, in a paper published in the journal Nature Communications, show on the contrary that they are highly dynamic. They move within the cell, remodel themselves, and can fuse with the nuclear envelope. Above all, they contain already-assembled nuclear pores, ready to be integrated into this envelope.
Annulate lamellae thus function as reservoirs of prefabricated pores. Formed in the cytoplasm, they accumulate these complexes and then fuse with the nuclear envelope to supply it with new functional pores. This mechanism is particularly active during the G1 phase of the cell cycle, the period during which the nucleus increases in size following cell division.
Using, in particular, super-resolution microscopy techniques made available by the Frisbi research infrastructure for biology and health, the scientists observed these structures in various normal human cells, including fibroblasts and neurons derived from stem cells. Annulate lamellae are therefore not a peculiarity of a few cell types or of cancer cells.
"We estimate that annulate lamellae contribute to roughly one-third of all newly assembled nuclear pores in dividing cells," explains Izabela Sumara. "This is not a minor pathway. It is a major new route for nuclear pore construction that had simply gone unnoticed."
Two proteins to build and deliver this reserve
The study also sheds light on how this pathway operates. In particular, it highlights the essential role of two proteins, RanBP2 — also known as Nup358 — and Climp63.
RanBP2 is itself a nucleoporin, that is, one of the proteins that make up nuclear pores. A particular region of this protein, rich in repeats of two amino acids, phenylalanine and glycine, promotes the clustering and assembly of pore components to form functional annulate lamellae.
Climp63 acts at a different step. This protein helps correctly position the pre-assembled pores on the membranes of the endoplasmic reticulum, an extensive membrane network of the cell that is continuous with the nuclear envelope. It thereby enables their delivery to the nucleus.
When RanBP2 or Climp63 is disrupted, the formation of new pores is compromised and the nucleus fails to grow normally in size. Annulate lamellae thus emerge as a genuine intermediate between pore manufacture in the cytoplasm and their incorporation into the nuclear envelope.
When the nuclear pore assembly pathway becomes dysregulated
This discovery could also shed light on certain pathological situations. The scientists found that various cellular stresses prevent annulate lamellae from properly reaching the nucleus. They then accumulate abnormally in the cytoplasm.
This is observed in particular when microtubules, components of the cell's internal cytoskeleton, are disrupted, but also when a protein involved in fragile X syndrome — a genetic disease that is a major cause of hereditary intellectual disability — is absent. Fibroblasts from individuals affected by this syndrome display markedly larger clusters of annulate lamellae.
These observations establish a link between dysregulation of this new pore-assembly pathway and certain nuclear abnormalities, without at this stage demonstrating that it is directly responsible for the disease.
The implications of these findings could extend further. Abnormal accumulations of nucleoporins in the cytoplasm have already been described in several cancers and neurodegenerative diseases. In some cases, these clusters could thus correspond to structures related to annulate lamellae whose formation, transport, or fusion with the nucleus has been disrupted.
"Does the abnormal accumulation of nucleoporins in the cytoplasm of patient cells contribute directly to the pathology? And could restoring nucleoporin balance constitute a therapeutic strategy? These are questions our laboratory is actively exploring," notes Dr. Lin, first author of the study.
A third pathway for building nuclear pores
By identifying the role of annulate lamellae, this work establishes a third, independent pathway of nuclear pore assembly in mammals, complementing the two mechanisms already known. When all three pathways are simultaneously disrupted, the density of pores present in the nuclear envelope decreases far more sharply than when only one of them is affected.
Cells thus have several complementary strategies at their disposal for building and renewing the thousands of pores required for the functioning and growth of their nucleus. The identification of this new pathway now calls for a reconsideration of the nucleoporin accumulations observed in certain diseases, and for determining whether restoring their normal organization could, in time, constitute a therapeutic avenue.
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CNRS BIOLOGIE - 3 september 2026 - https://www.insb.cnrs.fr/fr/cnrsinfo/une-usine-pores-nucleaires-decouverte-dans-nos-cellules
Learn more:
Lin J, Agote-Aran A, Liao Y, Cloarec M, Andronov L, Schoch RL, Ronchi P, Cochard V, Zhu R, Grandgirard E, Liu X, Lemée MV, Kleiss C, Golzio C, Ruff M, Chevreux G, Schwab Y, Klaholz BP, Sumara I.
"RanBP2-dependent annulate lamellae drive nuclear pore assembly and nuclear expansion".
Nature Communications, 25 mars 2026, DOI: 10.1038/s41467-026-71101-y. PMID: 41882018; PMCID: PMC13180977.
Contact:
Izabela Sumara
Directrice de Recherche DR1 CNRS
sumara@igbmc.fr