Probing the Cell’s Protein-Sorting Network

Four panels show blue cell nuclei surrounded by white dots representing ARMH3 against a black background. In the top panels, labeled WT, the white dots are highly concentrated just outside the nuclei. In the bottom panels, labeled ARL5 KO, the dots are distributed more diffusely.

ARL5 is required for ARMH3 to be recruited to the trans-Golgi network (TGN). ARMH3 (white) is expressed in typical cells (WT) and cells engineered to lack ARL5 (ARL5 KO). Images on right are magnified images of boxed areas. Note that ARMH3 is not recruited to the TGN in ARL5 KO cells. Cell nuclei are shown in blue. Scale bar represents 10 μm. 
Credit: Bonifacino Lab, NICHD

Small GTPases, including Arf-like GTPases (ARLs), are proteins that act as master regulators to integrate complex cellular processes. Researchers in the Bonifacino Lab study small GTPases, including ARL5, at the trans-Golgi network (TGN), where new proteins are modified, sorted, and distributed towards their final destinations in transport carriers.

  • Previously, the Bonifacino Lab found that ARL5 plays a key role in the retrieval of transport carrier machinery that is recycled back to the TGN. Their recent work revealed that ARL5 is also involved in lipid generation and protein modifications at the TGN through a newly identified interaction with the protein ARMH3.
  • ARL5 is necessary for recruitment of ARMH3 to the TGN. ARMH3 then activates the protein PI4KB, which produces most of the lipid PI4P in the TGN membrane. The interaction between ARMH3 and PI4KB promotes the replication of some viruses.
  • PI4P recruits the oncoprotein GOLPH3, which recruits and maintains glycosylation enzymes that modify glycans on newly synthesized proteins. Improper regulation of GOLPH3 results in cancer.
  • These findings elucidate the precise molecular mechanism by which a GTPase signaling cascade at the TGN, including ARL5, mediates the actions of ARMH3 and PI4KB. This work thus identifies multiple targets for antiviral and anticancer interventions.

Reference

Ishida M, Golding AE, Keren-Kaplan T, Li Y, Balla T, Bonifacino JS. ARMH3 is an ARL5 effector that promotes PI4KB-catalyzed PI4P synthesis at the trans-Golgi network. Nature Communications DOI: 10.1038/s41467-024-54410-y (2024)

Learn more about the Cell and Structural Biology group: https://www.nichd.nih.gov/about/org/dir/affinity-groups/CSB.

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