Subcellular location and activation of Tank Binding Kinase 1 (TBK1) govern precise progression through mitosis. Either loss of activated TBK1 or its sequestration from the centrosomes causes errors in mitosis and growth defects. Yet, what regulates its recruitment and activation on the centrosomes is unknown. We identified that NAK-associated protein 1 (NAP1) is essential for mitosis, binding to and activating TBK1, which both localize to centrosomes. Loss of NAP1 causes several mitotic and cytokinetic defects due to inactivation of TBK1. Our quantitative phosphoproteomics identified numerous TBK1 substrates that are not only confined to the centrosomes but are also associated with microtubules. Substrate motifs analysis indicates that TBK1 acts upstream of other essential cell cycle kinases like Aurora and PAK kinases. We also identified NAP1 as a TBK1 substrate phosphorylating NAP1 at S318 to promote its degradation by the ubiquitin proteasomal system. These data uncover an important distinct function for the NAP1-TBK1 complex during cell division.
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http://dx.doi.org/10.1083/jcb.202303082 | DOI Listing |
Nat Commun
November 2024
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA.
Cell death plasticity is crucial for modulating tissue homeostasis and immune responses, but our understanding of the molecular components that regulate cell death pathways to determine cell fate remains limited. Here, a CRISPR screen of acute myeloid leukemia cells identifies protein tyrosine phosphatase non-receptor type 23 (PTPN23) as essential for survival. Loss of PTPN23 activates nuclear factor-kappa B, apoptotic, necroptotic, and pyroptotic pathways by causing the accumulation of death receptors and toll-like receptors (TLRs) in endosomes.
View Article and Find Full Text PDFNat Struct Mol Biol
November 2024
Max Perutz Labs, Vienna Biocenter Campus (VBC), Vienna, Austria.
Mitophagy preserves overall mitochondrial fitness by selectively targeting damaged mitochondria for degradation. The regulatory mechanisms that prevent PTEN-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase Parkin (PINK1/Parkin)-dependent mitophagy and other selective autophagy pathways from overreacting while ensuring swift progression once initiated are largely elusive. Here, we demonstrate how the TBK1 (TANK-binding kinase 1) adaptors NAP1 (NAK-associated protein 1) and SINTBAD (similar to NAP1 TBK1 adaptor) restrict the initiation of OPTN (optineurin)-driven mitophagy by competing with OPTN for TBK1.
View Article and Find Full Text PDFJ Cell Biol
February 2024
School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
Sci Adv
August 2021
State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China.
The recruitment of Unc-51-like kinase and TANK-binding kinase 1 complexes is essential for Nuclear dot protein 52-mediated selective autophagy and relies on the specific association of NDP52, RB1-inducible coiled-coil protein 1, and Nak-associated protein 1 (5-azacytidine-induced protein 2, AZI2). However, the underlying molecular mechanism remains elusive. Here, we find that except for the NDP52 SKIP carboxyl homology (SKICH)/RB1CC1 coiled-coil interaction, the LC3-interacting region of NDP52 can directly interact with the RB1CC1 Claw domain, as that of NAP1 FIP200-binding region (FIR).
View Article and Find Full Text PDFDev Comp Immunol
June 2020
State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Science, Hunan Normal University, Changsha, 410081, China. Electronic address:
NAK-associated protein 1 (NAP1) is involved in NF-κB activation and interferon (IFN) induction in human and mammal; however, the role of teleost NAP1 in innate immunity remains unknown. In this paper, NAP1 homologue of black carp (Mylopharyngodon piceus) has been cloned and characterized. Black carp NAP1 (bcNAP1) migrated around 47 kDa in immunoblot assay and was identified as a cytosolic protein by immunofluorescent staining.
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