9LA9

Munc13-4-Rab27a complex with GppNHp

Summary for 9LA9

• Entry DOI: 10.2210/pdb9la9/pdb
• EMDB information: 62922
• Descriptor: Protein unc-13 homolog D, Ras-related protein Rab-27A, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER (3 entities in total)
• Functional Keywords: vesicle tethering, familial hemophagocytic lymphohistiocytosis type 3 /fhl3, griscelli syndrome type 2 /gs2, exocytosis
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 156858.49

Authors

Zheng, X.,Liu, C.Q.,Wang, S.,Guan, J.L.,He, J.,Ma, C. (deposition date: 2025-01-02, release date: 2025-10-01, Last modification date: 2025-10-29)

Primary citation

Liu, C.,Liu, D.,Zheng, X.,Guan, J.,Zhou, X.,Zhang, H.,Wang, S.,Li, Q.,Lu, G.,He, J.,Ma, C.
Munc13-4 mediates tumor immune evasion by regulating the sorting and secretion of PD-L1 via exosomes.
Nat Commun, 16:9080-9080, 2025

PubMed Abstract: Tumor-derived exosomes carry programmed death-ligand 1 (PD-L1), which binds programmed cell death protein 1 (PD-1) on T cells, suppressing immune responses locally and systemically. However, the mechanisms governing exosomal PD-L1 sorting and secretion remain elusive. Here, we identify Munc13-4 as a crucial regulator of this process. Deletion of Munc13-4 in breast tumors enhances T cell-mediated anti-tumor immunity, suppresses tumor growth, and improves the efficacy of immune checkpoint inhibitors. Mechanistically, Munc13-4 collaborates with hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), Rab27, and SNAREs to facilitate PD-L1 sorting and secretion via exosomes. Cryogenic electron microscopy (cryo-EM) analysis of the Munc13-4-Rab27a complex provide structural insights into exosome secretion. Importantly, PD-L1 sorting relies on a ternary complex composed of Munc13-4, PD-L1 and HRS, which is regulated by interferon gamma (IFNγ) signaling. A designed peptide that disrupts Munc13-4-PD-L1 interaction impedes PD-L1 sorting, enhances antitumor immunity, and suppresses tumor growth, highlighting the therapeutic potential of targeting this pathway.

PubMed: 41083534
DOI: 10.1038/s41467-025-64149-9

Experimental method

ELECTRON MICROSCOPY (4.38 Å)