Hypersensitivity of Vps33B mutant flies to non‐pathogenic infections is dictated by aberrant activation of p38b MAP kinase. (3rd August 2020)

• Record Type: Journal Article
• Authors: Zhang, Jian; Tracy, Charles; Pasare, Chandrashekhar; Zeng, Jinsheng; Krämer, Helmut
• Is Part Of: Traffic. Volume 21:Number 9(2020)
• Page Start: 578
• Page End: 589
• Publication Date: 2020-08-03
• Subjects: endosomes -- innate immune system -- lysosomal delivery -- macropinocytosis -- PGRP‐LC -- phagocytosis; Biological transport -- Periodicals; 571.6
• DOI: 10.1111/tra.12756
• Languages: English
• ISSNs: 1398-9219

Abstract

Abstract: Loss of the arthrogryposis‐renal dysfunction‐cholestasis (ARC) syndrome‐linked Vps33B protein results in exaggerated inflammatory responses upon activation of receptors of the innate immune system in both vertebrates and flies. However, little is known about the signaling elements downstream of these receptors that are critical for the hypersensitivity of Vps33B mutants. Here, we show that p38b MAP kinase contributes to the enhanced inflammatory responses in flies lacking Vps33B . Loss of p38b mitogen‐activated protein kinase (MAPK) reduces enhanced inflammatory responses and prolongs the survival of infected Vps33B deficient flies. The function of p38 MAPK is not limited to its proinflammatory effects downstream of the PGRP‐LC receptor as p38 also modulates endosomal trafficking of PGRP‐LC and phagocytosis of bacteria. Expression of constitutively active p38b MAPK, but not dominant negative p38b MAPK enhances accumulation of endocytosed PGRP‐LC receptors or phagocytosed bacteria within cells. Moreover, p38 MAPK is required for induction of macropinocytosis, an alternate pathway for the downregulation of immune receptors. Together, our data indicate that p38 MAPK activates multiple pathways that can contribute to the dysregulation of innate immune signaling in ARC syndrome. Abstract : Mutations in Vps33B or VIPAS39 cause ARC syndrome, a lethal disease with frequent infections and sepsis. Here, we model aspects of ARC syndrome in Drosophila. In Vps33B mutant cells of the innate immune system, activated pattern recognition receptors accumulate in aberrant endosomes and persistently activate downstream signaling. The resulting lethality is mediated by p38b mitogen‐activated protein kinase (MAPK) involving two distinct mechanisms. Downstream of receptors, p38b MAPK signaling triggers excessive cytokine expression, and upstream it promotes further receptor uptake establishing a deleterious feed‐forward loop.