Regulation of phagocyte triglyceride by a STAT-ATG2 pathway controls mycobacterial infection
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Published version
OA Location
Author(s)
Type
Journal Article
Abstract
Mycobacterium tuberculosis
remains a global threat to human health yet the
molecular mechanisms reg
ulating immunity remain poorly understood.
Cytokines can
promote or inhibit
mycobacteria
l
survival
inside macrophages
, and
the underlying
mechanisms represent potential targets for host
-
directed therapies
.
Here w
e show t
hat
cytokine
-
STAT signaling
promote
s
mycobacterial
survival
within macrophages by
deregulatin
g lipid droplets via ATG2 repression
.
I
n
Drosophila
infected with
Mycobacterium marinum
,
mycobacterium
-
induced STAT
activity
triggered by
unpaired
-
family
cytokines
reduces
Atg2
expression
, permitting
deregulation of lipid
droplets. Increased
Atg2
expression
, or reduced macrophage triglyceride biosynthesis,
normalize
s
lipid deposition in infected phagocytes and
reduces numbers
of
viable
intracellular
mycobacteria.
I
n human macrophages,
addition of
IL
-
6
promotes
mycobacterial survival and BCG
-
induced lipid accumulation by a similar, but
probably not identical, mechanism
. Our results reveal
Atg2
regulation as a
mechanism
by which cytokines
can
control lipid droplet homeostasis and consequently resistance
to mycobacterial infection
in
Drosophila
.
remains a global threat to human health yet the
molecular mechanisms reg
ulating immunity remain poorly understood.
Cytokines can
promote or inhibit
mycobacteria
l
survival
inside macrophages
, and
the underlying
mechanisms represent potential targets for host
-
directed therapies
.
Here w
e show t
hat
cytokine
-
STAT signaling
promote
s
mycobacterial
survival
within macrophages by
deregulatin
g lipid droplets via ATG2 repression
.
I
n
Drosophila
infected with
Mycobacterium marinum
,
mycobacterium
-
induced STAT
activity
triggered by
unpaired
-
family
cytokines
reduces
Atg2
expression
, permitting
deregulation of lipid
droplets. Increased
Atg2
expression
, or reduced macrophage triglyceride biosynthesis,
normalize
s
lipid deposition in infected phagocytes and
reduces numbers
of
viable
intracellular
mycobacteria.
I
n human macrophages,
addition of
IL
-
6
promotes
mycobacterial survival and BCG
-
induced lipid accumulation by a similar, but
probably not identical, mechanism
. Our results reveal
Atg2
regulation as a
mechanism
by which cytokines
can
control lipid droplet homeostasis and consequently resistance
to mycobacterial infection
in
Drosophila
.
Date Issued
2017-03-06
Date Acceptance
2017-01-18
Citation
Nature Communications, 2017, 8, pp.1-11
ISSN
2041-1723
Publisher
Nature Publishing Group
Start Page
1
End Page
11
Journal / Book Title
Nature Communications
Volume
8
Copyright Statement
© 2017 The Authors. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Sponsor
Biotechnology and Biological Sciences Research Council (BBSRC)
Medical Research Council
Identifier
https://www.nature.com/articles/ncomms14642
Grant Number
BB/L020122/2
MR/L018802/2
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
M. TUBERCULOSIS INFECTION
DROSOPHILA-MELANOGASTER
IMMUNE-RESPONSES
GENE-EXPRESSION
LIPID DROPLETS
HOST-DEFENSE
MACROPHAGES
HOMEOSTASIS
AUTOPHAGY
CYTOKINES
Animals
Autophagy-Related Proteins
Cell Line
Disease Models, Animal
Disease Resistance
Drosophila
Drosophila Proteins
Hemocytes
Humans
Interleukin-6
Macrophages
Male
Mycobacterium Infections
Mycobacterium bovis
Mycobacterium marinum
Mycobacterium tuberculosis
Primary Cell Culture
STAT Transcription Factors
Signal Transduction
Triglycerides
Vesicular Transport Proteins
Virulence
Hemocytes
Cell Line
Macrophages
Animals
Humans
Drosophila
Mycobacterium marinum
Mycobacterium bovis
Mycobacterium tuberculosis
Mycobacterium Infections
Disease Models, Animal
Triglycerides
Drosophila Proteins
Vesicular Transport Proteins
Interleukin-6
Virulence
Signal Transduction
Male
STAT Transcription Factors
Primary Cell Culture
Disease Resistance
Autophagy-Related Proteins
Publication Status
Published
Article Number
14642
Date Publish Online
2017-03-06