SYNE3

Nesprin-3 (SYNE3) is an outer nuclear membrane component of the LINC complex that couples the nucleus to the intermediate filament cytoskeleton, thereby maintaining perinuclear cytoskeletal architecture, nuclear shape, and mechanotransduction (PMID:16330710, PMID:21937718). Unlike actin-binding nesprins, it lacks an actin-binding domain and instead recruits the plakin crosslinker plectin to the nuclear perimeter, connecting the nucleus to the intermediate filament network (PMID:16330710). Its retention at the outer nuclear membrane requires the C-terminal KASH domain, whose terminal residues mediate interaction with Sun1 and Sun2 at the inner nuclear membrane; loss of these residues or of Sun proteins redistributes nesprin-3 to the ER (PMID:17881500). The plectin interaction depends on plectin dimerization and on specific residues (R43, L44) in nesprin-3's first spectrin repeat, and in vivo loss of nesprin-3 reduces perinuclear concentration of intermediate filaments and displaces plectin and vimentin from the nuclear envelope (PMID:17881500, PMID:21303928, PMID:23761073). Functionally, nesprin-3 is required for centrosome attachment to the nuclear envelope, flow-induced polarization and migration in endothelial cells, and for transmitting vimentin-borne forces that set nuclear envelope tension and resist nuclear deformation (PMID:21937718, PMID:42168662, PMID:39554181). In oncogenic KRAS pancreatic cancer cells, KLF5-driven SYNE3 upregulation supports an Emerin–nesprin-3 interaction required for mKRAS-induced nuclear morphology changes and proliferation (PMID:42175908). Notably, nesprin-3 knockout mice are fertile with normal Sertoli cell nuclear positioning, indicating the nesprin-3–plectin–IF link is dispensable for some developmental contexts (PMID:23761073).

1. 2005 High

   Established that an outer nuclear membrane nesprin could link the nucleus to the cytoskeleton independently of actin, defining nesprin-3 as the intermediate-filament arm of nuclear-cytoskeletal coupling.

   Evidence Protein isolation, overexpression, colocalization, and co-IP showing plectin recruitment to the nuclear perimeter with keratins

   PMID:16330710

   Open questions at the time

   • Did not define how nesprin-3 itself is anchored at the nuclear envelope
   • Functional consequence of the IF link for nuclear behavior not tested
2. 2007 High

   Defined the molecular basis for nesprin-3 anchoring and its plectin interaction, placing nesprin-3 within the LINC complex via KASH-Sun coupling.

   Evidence Deletion mutagenesis, siRNA knockdown of Sun proteins, and co-IP in cultured cells

   PMID:17881500

   Open questions at the time

   • In vivo relevance of the KASH-Sun interaction not established
   • Functional role of actin-regulated plectin binding unclear
3. 2011 Medium

   Demonstrated a cellular function for nesprin-3 in endothelial mechanobiology, linking it to centrosome anchoring and flow-induced polarization and migration.

   Evidence siRNA knockdown with live imaging and flow-chamber assays in human aortic endothelial cells

   PMID:21937718

   Open questions at the time

   • Single-lab knockdown without genetic confirmation
   • Mechanism connecting nesprin-3 to centrosome positioning not resolved
4. 2011 High

   Pinpointed the spectrin-repeat residues required for plectin binding and confirmed in vivo that nesprin-3 concentrates intermediate filaments around the nucleus.

   Evidence Zebrafish loss-of-function, residue-level mutagenesis, and co-IP

   PMID:21303928

   Open questions at the time

   • Overlap with integrin-binding plectin residues raises competition questions not resolved
   • Physiological consequence of reduced perinuclear IF in zebrafish unclear
5. 2011 Low

   Extended nesprin-3 connectivity to microtubules via BPAG1 and MACF, broadening the cytoskeletal systems it could bridge.

   Evidence Interaction studies cited in a review synthesis

   PMID:22103514

   Open questions at the time

   • Reported in review without primary experimental detail in the source
   • No functional consequence of microtubule linkage demonstrated
6. 2013 High

   Tested organismal requirement for nesprin-3, showing it anchors plectin and vimentin at the nuclear envelope but is dispensable for fertility and fibroblast migration.

   Evidence Nesprin-3 knockout mouse, immunofluorescence, histology, and fertility assays

   PMID:23761073

   Open questions at the time

   • Redundancy with other nesprins not directly tested
   • Contexts where the IF link is non-redundant remain unidentified
7. 2024 Medium

   Established nesprin-3 as the mechanical conduit through which vimentin sets nuclear envelope tension and protects against nuclear deformation.

   Evidence siRNA knockdown, vimentin-null cells, micropatterning, and FRET nuclear-envelope tension sensors

   PMID:39554181 PMID:42168662

   Open questions at the time

   • Single-lab mechanical readouts
   • Whether nesprin-3 binds vimentin directly or via plectin not disentangled here
8. 2026 Medium

   Identified an Emerin–nesprin-3 interaction induced by oncogenic KRAS that is required for cancer-associated nuclear morphology and proliferation.

   Evidence BioID proximity labeling, transcriptomic/epigenomic profiling, knockdown, and interaction-deficient Emerin mutant rescue in pancreatic cancer cells

   PMID:42175908

   Open questions at the time

   • Single-lab finding limited to oncogenic KRAS context
   • Direct versus proximity-based nature of the Emerin interaction not fully resolved

• How nesprin-3 integrates intermediate-filament, microtubule, and Emerin linkages to control nuclear shape and force transmission across normal tissues remains unresolved.
• No structural model of the nesprin-3 LINC assembly
• Tissue contexts where nesprin-3 is non-redundant unknown
• Direct vimentin-binding interface uncharacterized