bims-nakice 2026-09-13 papers

Issue of 2026–09–13
nine papers selected by
Santosh Phuyal, Oslo Universitetssykehus

Nat Commun. 2026 Aug 08. pii: 9527. [Epub ahead of print]17(1):

Macrophages tune NK cell IFNγ production through direct lipid transfer.

Cathal Keane, Shauna Mayock, Carrie Corkish, Ella Rogerson, Cristhiane Favero de Aguiar, Ya Gao, Sarah Kenny, Lorraine Brennan, Suzanne M Cloonan, David K Finlay.

Natural killer (NK) cells are critical effectors of innate immunity, but their activity is strongly influenced by metabolic state. While intrinsic NK metabolism has been studied extensively, less is known about how surrounding immune cells shape NK cell function. Here, we identify a direct metabolic communication axis between macrophages and NK cells. Using co-culture and in vivo models, we show that lipopolysaccharide-stimulated macrophages induce lipid accumulation in NK cells that suppresses mTORC1 activity and the production of IFNγ. This lipid accumulation is visualised as increased lipid droplets content in NK cells, generated using fatty acids synthesised within the macrophages. Genetic and pharmacological approaches show that fatty acid transfer from macrophages to NK cells requires cell-cell contact and is associated with CD36 protein transfer via trogocytosis. Blocking fatty acid synthesis specifically in macrophages prevents lipid accumulation in NK cells and restores both mTORC1 activity and IFNγ production. These findings define a previously unrecognized mechanism of macrophage-NK cell cross-regulation, revealing how metabolic exchange constrains NK effector function and establishing a feedback circuit with implications for hyperinflammation and immunotherapy.

DOI: https://doi.org/10.1038/s41467-026-76444-0

J Biol Chem. 2026 Sep 08. pii: S0021-9258(26)02415-4. [Epub ahead of print] 113543

Siglec-7 orchestrates mitochondrial dynamics and metabolic reprogramming to restrain human NK cell cytotoxic function.

Shih-Chi Su, Nai-Ting Tsao, Tzu-Ling Wang, Yi-Chen Shih, Yuh-Ching Twu.

Natural killer (NK) cells are innate lymphocytes that directly eliminate tumor and virus-infected cells by integrating signals from activating and inhibitory receptors, and their effector functions are tightly coupled to cellular metabolism. Given that the inhibitory receptor PD-1 reprograms T cell metabolism to shape functional fate, the bioenergetic consequences of inhibitory receptor engagement on human NK cells remain largely unexplored, particularly for sialic acid-binding immunoglobulin-like lectin (Siglec-7), a glyco-immune checkpoint receptor. Here, we investigated metabolic programs and effector functions associated with Siglec-7 expression and antibody-mediated Siglec-7 ligation in primary NK cells and NK-92MI cells. Siglec-7POS NK cells exhibited selectively impaired CD107a degranulation under glycolytic and oxidative phosphorylation inhibition, whereas Siglec-7NEG cells remained relatively resistant, indicating distinct energetic wiring between these subsets. Engagement of Siglec-7 by an agonistic antibody induced mitochondrial fission with altered Drp1 phosphorylation, transient mitochondrial depolarization, and broadly suppressed mitochondrial respiration, while concurrently enhancing glycolytic capacity, consistent with a dual metabolic shift upon Siglec-7 ligation. In contrast, sustained Siglec-7 expression in NK-92MI-S cells was associated with globally enhanced mitochondrial respiratory capacity, indicating that sustained Siglec-7 expression and short-term treatment with an agonistic anti-Siglec-7 antibody were associated with distinct metabolic profiles in NK cells. Furthermore, Siglec-7POS NK cells showed increased accumulation of autophagic vacuole, reduced proliferation, and heightened apoptotic susceptibility compared with Siglec-7NEG counterparts. Collectively, these findings support an association between Siglec-7 status, mitochondrial homeostasis, and metabolic fitness in NK cells, with Siglec-7NEG cells retaining a metabolically robust, cytotoxic phenotype.

DOI: https://doi.org/10.1016/j.jbc.2026.113543

iScience. 2026 Sep 18. 29(9): 117350

Identification of elements determining KIR gene demethylation at the CD56-bright stage of NK cell development.

Hongchuan Li, Noah T Koenigs, Michael Ruesch, Ella Troy, Olivia Brancato-Buentello, Zhonghe Sun, Xiaolin Wu, Xiongfong Chen, Yongmei Zhao, Aharon G Freud, Stephen K Anderson.

The variegated expression of the KIR family of class I MHC receptors generates specialized natural killer (NK) cells capable of allele-specific HLA recognition. Understanding the mechanism of KIR gene activation will lead to improved methods for the generation of fully functional NK cells. A central RUNX-binding site in the KIR proximal promoter is required for gene activation. RUNX proteins recruit ten-eleven translocation (TET) proteins that generate 5-hydroxymethylcytosine (5hmC) and drive DNA demethylation. Assessment of 5-methylcytosine (5mC) and 5hmC residues at four stages of NK cell development reveals deposition of 5hmC primarily in a CREB site next to the RUNX site at the CD56Bright stage but not the subsequent CD56Dim stage representing fully mature NK cells. KIR promoter demethylation is delayed relative to other lineage-associated genes, indicating a high threshold for KIR gene demethylation in developing NK cells, and a window of opportunity for RUNX/TET-dependent KIR gene activation in CD56Bright NK cells.

Keywords: 6-base sequencing; KIR; NK cells; TET2; epigenetic regulation; human; hydroxymethylcytosine

DOI: https://doi.org/10.1016/j.isci.2026.117350

Nature. 2026 Sep;657(8131): 562-564

Probing the proteome at cellular scale.

Michael Eisenstein.

Keywords: Biological techniques; Cell biology; Proteomics; Technology

DOI: https://doi.org/10.1038/d41586-026-02805-w

STAR Protoc. 2026 Sep 08. pii: S2666-1667(26)00473-9. [Epub ahead of print]7(3): 104820

Protocol for fluorescence-activated mitochondria sorting in endoplasmic reticulum-mitochondria contact reporter cells.

Drew C Stark, Brandon Chen, Kayla Hickman, Costas A Lyssiotis, Yatrik M Shah.

Mitochondria exchange metabolites bidirectionally with the endoplasmic reticulum to maintain bioenergetic homeostasis and respond to cellular stress. Here, we describe a protocol for generating cells that contain a split-GFP contact-site reporter of ER-mitochondria interactions and the sorting of heterogeneous mitochondrial populations based on fluorescence intensity. This approach enables reproducible functional profiling of mitochondrial subpopulations, validated by proteomic analysis demonstrating the enrichment of endoplasmic reticulum-associated proteins in GFP-positive mitochondria. For complete details on the use and execution of this protocol, please refer to Chen et al.1.

Keywords: Cell Biology; Cell separation/fractionation; Flow Cytometry; Metabolism

DOI: https://doi.org/10.1016/j.xpro.2026.104820

Cell Rep. 2026 Sep 09. pii: S2211-1247(26)01053-3. [Epub ahead of print]45(9): 117975

Mitochondrial Raf1 regulates glutamine catabolism.

Ronald L Shanderson, Ian D Ferguson, Luca Ducoli, Weili Miao, Suhas Srinivasan, Zurab Siprashvili, Albert M Li, Mary Grace Velasco, Yang Li, Christine N Hoang, Jiangbin Ye, Paul A Khavari.

Raf kinases are central to mitogenic signaling and cancer, yet the full complement of functionally important Raf-proximal proteins across subcellular compartments remains undefined. Here, proximity-dependent biotinylation (BioID) of Raf1 in Raf1-dependent cancer cells recovered proteins localized to the mitochondrial matrix. Mitochondrial purification and super-resolution microscopy confirmed that a pool of Raf1 resides within mitochondria. There, Raf1 associated with glutaminase (GLS) across diverse human cancers and enabled glutaminolysis, a major source of biosynthetic precursors in tumor cells. These effects required Raf1 kinase activity but were independent of canonical MAP kinase pathway signaling, and matrix-targeted kinase-dead Raf1 impaired both glutaminolysis and in vivo tumorigenesis. Raf1 therefore acts inside mitochondria, where it engages GLS to drive glutamine catabolism and support tumor growth, revealing a non-canonical, metabolic arm of Raf signaling.

Keywords: CP: metabolism; MAPK; Raf1; glutaminase; metabolic reprograming

DOI: https://doi.org/10.1016/j.celrep.2026.117975

Dev Cell. 2026 Sep 09. pii: S1534-5807(26)00316-3. [Epub ahead of print]61(9): 1749-1751

Between adaptation and cell death: An ER-localized transcription factor controls cell fate.

Jiaqi Sun, Huanquan Zheng.

Rooted in place, plants must continually balance adaptation and cell death under environmental stress. In this issue of Developmental Cell, Yang et al. demonstrate that NAC089, an ER-localized transcription factor, acts as a molecular switch that determines these alternative outcomes under different environmental conditions.

DOI: https://doi.org/10.1016/j.devcel.2026.08.005

Nature. 2026 Sep;657(8131): S14-S15

Drug delivery gets subcellular.

Katherine Bourzac.

Keywords: Cell biology; Therapeutics

DOI: https://doi.org/10.1038/d41586-026-02659-2

Cell Rep. 2026 Sep 09. pii: S2211-1247(26)01072-7. [Epub ahead of print]45(9): 117994

Mitochondrial Fis1 tunes Rab7A activity via TBC1D15 modulating STING degradation.

Eunice Dominguez-Martin, Linlin Lei, Jennifer D Petersen, Peng-Peng Zhu, Katherine R Tucker, Richard J Youle.

The mechanisms governing the final trafficking steps of the cyclic dinucleotide innate immune receptor stimulator of interferon genes (STING) are not fully understood. Here, we identify the mitochondrial protein Fis1 as a regulator of STING endolysosomal degradation. The absence of Fis1 in HeLa cells stabilizes STING, boosting downstream signaling without affecting its initial endoplasmic reticulum (ER)-to-Golgi traffic. Instead, Fis1 loss impairs STING delivery to endolysosomes. Fis1 recruits the Rab7A-GAP TBC1D15 to mitochondria and upon STING activation, TBC1D15 localization shifts to the Golgi. In the absence of Fis1, the interaction between TBC1D15 and Rab7A is disrupted, leading to decreased Rab7A GTPase activity and impaired STING degradation. Our findings reveal a mitochondria-controlled axis where Fis1 tunes Rab7A activity via TBC1D15, which is required to ensure proper STING degradation, directly linking mitochondria to lysosomal trafficking and the termination of innate immune signaling.

Keywords: CP: cell biology; CP: immunology; Fis1; Golgi; Rab-GAP; Rab7; STING; TBC1D15; innate immunity; lysosomal degradation; mitochondria; traffic

DOI: https://doi.org/10.1016/j.celrep.2026.117994