TY - JOUR
T1 - PIM1 controls GBP1 activity to limit self-damage and to guard against pathogen infection
AU - Fisch, Daniel
AU - Pfleiderer, Moritz M
AU - Anastasakou, Eleni
AU - Mackie, Gillian M
AU - Wendt, Fabian
AU - Liu, Xiangyang
AU - Clough, Barbara
AU - Lara-Reyna, Samuel
AU - Encheva, Vesela
AU - Snijders, Ambrosius P
AU - Bando, Hironori
AU - Yamamoto, Masahiro
AU - Beggs, Andrew D
AU - Mercer, Jason
AU - Shenoy, Avinash R
AU - Wollscheid, Bernd
AU - Maslowski, Kendle M
AU - Galej, Wojtek P
AU - Frickel, Eva-Maria
PY - 2023/10/6
Y1 - 2023/10/6
N2 - Disruption of cellular activities by pathogen virulence factors can trigger innate immune responses. Interferon-γ (IFN-γ)-inducible antimicrobial factors, such as the guanylate binding proteins (GBPs), promote cell-intrinsic defense by attacking intracellular pathogens and by inducing programmed cell death. Working in human macrophages, we discovered that GBP1 expression in the absence of IFN-γ killed the cells and induced Golgi fragmentation. IFN-γ exposure improved macrophage survival through the activity of the kinase PIM1. PIM1 phosphorylated GBP1, leading to its sequestration by 14-3-3σ, which thereby prevented GBP1 membrane association. During Toxoplasma gondii infection, the virulence protein TgIST interfered with IFN-γ signaling and depleted PIM1, thereby increasing GBP1 activity. Although infected cells can restrain pathogens in a GBP1-dependent manner, this mechanism can protect uninfected bystander cells. Thus, PIM1 can provide a bait for pathogen virulence factors, guarding the integrity of IFN-γ signaling.
AB - Disruption of cellular activities by pathogen virulence factors can trigger innate immune responses. Interferon-γ (IFN-γ)-inducible antimicrobial factors, such as the guanylate binding proteins (GBPs), promote cell-intrinsic defense by attacking intracellular pathogens and by inducing programmed cell death. Working in human macrophages, we discovered that GBP1 expression in the absence of IFN-γ killed the cells and induced Golgi fragmentation. IFN-γ exposure improved macrophage survival through the activity of the kinase PIM1. PIM1 phosphorylated GBP1, leading to its sequestration by 14-3-3σ, which thereby prevented GBP1 membrane association. During Toxoplasma gondii infection, the virulence protein TgIST interfered with IFN-γ signaling and depleted PIM1, thereby increasing GBP1 activity. Although infected cells can restrain pathogens in a GBP1-dependent manner, this mechanism can protect uninfected bystander cells. Thus, PIM1 can provide a bait for pathogen virulence factors, guarding the integrity of IFN-γ signaling.
UR - http://www.scopus.com/inward/record.url?scp=85174751781&partnerID=8YFLogxK
U2 - 10.1126/science.adg2253
DO - 10.1126/science.adg2253
M3 - Article
C2 - 37797010
SN - 0036-8075
VL - 382
JO - Science
JF - Science
IS - 6666
M1 - eadg2253
ER -