Kondo Naoyuki, Mimori-Kiyosue Yuko, Tokuhiro Keizo, Pezzotti Giuseppe, Kinashi Tatsuo
Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan.
Department of Genome Editing, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan.
Nat Commun. 2025 Feb 4;16(1):1343. doi: 10.1038/s41467-025-56631-1.
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.
白细胞整合素LFA1对免疫反应至关重要，它协调淋巴细胞的运输和黏附。虽然LFA1激活通过由外向内信号传导诱导LFA1在细胞接触表面聚集，但其调节机制仍不清楚。在这里，我们发现了自噬体成分LC3在自噬作用之外的一个以前未被发现的功能，即通过连接两条看似不相关的途径：LFA1运输和自噬体运输。LFA1聚集体与LC3共同运输，促进LFA1在接触表面的积累。LC3b基因敲除降低了淋巴细胞黏附性。LFA1激活并未诱导自噬，然而它增加了mTOR和AMPK的活性。LFA1依赖的AMPK激活增强了LFA1和LC3的聚集及黏附。抑制Mst1激酶介导的LC3磷酸化通过与RAPL的直接相互作用促进了LC3介导的LFA1募集到接触表面，揭示了一条前所未有的整合素募集途径。这些发现揭示了LC3的一种功能，并扩展了我们对通过LFA1进行淋巴细胞调节的理解。
