Autophagy as a tumor suppressor in normal cells

isolate cargo a into the membrane with   double
structure commonly referred by autophagosome5. Induction of autophagy can be
monitored by MAP1LC3B (LC3) formation5. To survive inside macrophages,
intracellular bacteria develope a variety of strategies to avoid or fight the
host defence system13. In this case, MTB has the ability to hold phagosome

can act as a tumor suppressor in normal cells based on the efficiency of
non-apoptotic cell death from malignant cells and DNA damage by inhibiting ROS
formation18. Antimicrobial activity and apoptosis of human macrophages can be
triggered by cytosolic phospholipase activity through MTB which catalyze the
release of arachidonic acid. Arachidonic acid is product of a second messenger
of TNF which induce apoptosis and oxygen radicals, which are produced during
arachidonic acid lipoxygenation, thus inducing the production of reactive
oxidative species and are involved in cell death4.

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that are resistant to drugs is a threat to human health. Resistant to
antibiotics can be against two things: bacterial survival ability and the
ability to reproduce in the presence of macrophages. When bacteria enters the
macrophages, they will experience environmental stress such as nutritional
restriction induced by the host, acidification, toxic peptides, osmotic stress,
and reactive oxygen species (ROS), which later became the biggest cause the
death of the bacteria16. To survive inside macrophages, MTB developed a variety
of strategies to avoid or fight the host defence system13. One of the
mechanisms of MTB to survive is manipulating the host cell death pathways in
infected cells. One of the virulence factors are surface glycolipid PDIM
(phthiocerol dimycocerosates)21. Lipid are not directly genetically encoded and
therfore are not amenable to traditional tagging methods, also cell wall lipids
have mutiple overlapping functions16. Multiple role functions from PDIM on
pathogenesis has been investigated before, including the invasion of
macrophages, masking of pathogen-associated molecular pattern (PAMPS),
resistance to death with nitric oxide, and the prevention of the recruitment of
active macrophages to infected area19. PDIM supress recruitment of         microbicidal,   iNOS-positive

by inhibiting TLR signaling (Figure 3)24. Interactions between host and bacterial
cell wall are likely to be bidirectonal and change when infection24. PDIM in
vivo21abundance depend on expression of bisynthetic enzymes which decrease upon
macrophage infection, shift metabolic flux which occur during host lipid
catabolism10 and insertion of molecule into host membranes1. There maybe
variable amount of PDIM on MTB surface at different time points after

            MTB initiated human infections in
distal lung, and reside in upper respiratory tract. TLR signalling stimulated
by PAMPs from lung overrides PDIM and PGL-mediated immune evasion24. There is
site named resistance-determining region (RRDR)22 that caused by mutations in
MTB strains at 81-bp region of rpoB. This mutations result is high levels of
resistance to rifampicin.

to Comas7 all laboratory-generated mutans of MTB with
rifampicin-resistance  mutations in the
RRDR reduced fitness compared to their respond for drug ancestors when without
rifampicin8, MTB with RIF resistant caused by mutations in the rpoB gene, where
the majority is on codon 531 and 52612. According to Kawamura mutation in codon
526 related to oxidative stress sensitivity14. In addition, some reports say
that just one gene mutations in the rpoB encodes in sub-unit of RNA polymerase
? can cause interaction between the RNA polymerase and some promoter also
transcription regulation that trigger changes in phenotype16.

mechanism of the rpoB gene mutation caused by resistant rifampicin indicates
that specific lead to mutations in the rpoB changes aspects of transcription.
These transcription factors causing changes in gene expression which encodes
the protein secretion, and proteomic changes produce some enzymes and lipid
biosynthetic of intermediate in the path of phthiocerol dymycocerosate (PDIM).
To prove PDIM plays role in induction of autophagy and necrosis on MTB, Quigley
observed conversion of cytosolic LC3I to autophagosome-bound LC3II, using the
expression of green fluorescent protein-LC3 (GFP) and flow cytometry21. As a
result, autophagy was decreased in cells infected by MTB. PDIM plays role in
induction of autophagy with decreasing autophagy on infected cells by MTB21.

to rifampicin caused by mutations in rpoB gene related with physiological  and metabolic changes in bacterial systems
(Koch). These RIF resistance might be under dual selection in MTB, combined
benefit and physiological advantage of rpoB gene can fix rpoB mutants to infect
in MTB populations.



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