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Abstract ACE2 on epithelial cells is the SARS‐CoV‐2 entry receptor. Single‐cell RNA‐sequencing data derived from two COVID‐19 cohorts revealed that MAP4K3/GLK‐positive epithelial cells were increased in patients. SARS‐CoV‐2‐induced GLK overexpression in epithelial cells was correlated with COVID‐19 severity and vesicle secretion. GLK overexpression induced the epithelial cell‐derived exosomes containing ACE2; the GLK‐induced exosomes transported ACE2 proteins to recipient cells, facilitating pseudovirus infection. Consistently, ACE2 proteins were increased in the serum exosomes from another COVID‐19 cohort. Remarkably, SARS‐CoV‐2 spike protein‐stimulated GLK, and GLK stabilized ACE2 in epithelial cells. Mechanistically, GLK phosphorylated ACE2 at two serine residues (Ser776, Ser783), leading to the dissociation of ACE2 from its E3 ligase UBR4. Reduction in UBR4‐induced Lys48‐linked ubiquitination at three lysine residues (Lys26, Lys112, Lys114) of ACE2 prevented its degradation. Furthermore, SARS‐CoV‐2 pseudovirus or live virus infection in humanized ACE2 mice induced GLK and ACE2 protein levels, and ACE2‐containing exosomes. Collectively, ACE2 stabilization by SARS‐CoV‐2‐induced MAP4K3/GLK may contribute to the pathogenesis of COVID‐19.

Dual-specificity phosphatase 11 (DUSP11, also named as PIR1) is a member of the atypical DUSP protein tyrosine phosphatase family. DUSP11 is only known to be an RNA phosphatase that regulates noncoding RNA stability. To date, the role of DUSP11 in immune cell signaling and immune responses remains unknown. In this study, we generated and characterized the immune cell functions of DUSP11-deficient mice. We identified TGF-β-activated kinase 1 (TAK1) as a DUSP11-targeted protein. DUSP11 interacted directly with TAK1, and the DUSP11-TAK1 interaction was enhanced by LPS stimulation in bone marrow-derived macrophages. DUSP11 deficiency enhanced the LPS-induced TAK1 phosphorylation and cytokine production in bone marrow-derived macrophages. Furthermore, DUSP11-deficient mice were more susceptible to LPS-induced endotoxic shock. The LPSinduced serum levels of IL-1β, TNF-α, and IL-6 were significantly elevated in DUSP11-deficient mice compared with those of wild-type mice. The data indicate that DUSP11 inhibits LPS-induced macrophage activation by targeting TAK1. [ABSTRACT FROM AUTHOR]