The autophagy component LC3 regulates lymphocyte adhesion via LFA1 transport in response to outside-in signaling

Naoyuki Kondo (), Yuko Mimori-Kiyosue, Keizo Tokuhiro, Giuseppe Pezzotti and Tatsuo Kinashi
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Naoyuki Kondo: Kansai Medical University
Yuko Mimori-Kiyosue: Kansai Medical University
Keizo Tokuhiro: Kansai Medical University
Giuseppe Pezzotti: Kansai Medical University
Tatsuo Kinashi: Kansai Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract The leukocyte integrin LFA1 is indispensable for immune responses, orchestrating lymphocyte trafficking and adhesion. While LFA1 activation induces LFA1 clustering at the cell contact surface via outside-in signaling, the regulatory mechanisms remain unclear. Here, we uncovered a previously hidden function of the autophagosome component LC3 beyond its role in autophagy by bridging two seemingly unrelated pathways: LFA1 transport and autophagosome transport. LFA1 clusters co-trafficked with LC3, facilitating LFA1 accumulation at the contact surface. LC3b knockout decreased lymphocyte adhesiveness. LFA1 activation did not induce autophagy, whereas it increased mTOR and AMPK activity. LFA1-dependent AMPK activation enhances LFA1 and LC3 clustering and adhesion. Inhibiting Mst1 kinase-mediated LC3 phosphorylation promoted LC3-mediated LFA1 recruitment to the contact surface through direct interaction with RAPL, uncovering an unprecedented integrin recruitment route. These findings uncover a function of LC3 and expand our understanding of lymphocyte regulation via LFA1.

Date: 2025
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DOI: 10.1038/s41467-025-56631-1

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