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Cell-Autonomous Immunity
eign DNA in a sequence-specific manner (2). In
metazoans, cellular self-defense synergizes with
the whole-body protection provided by traditional
1
he cell is an outstandingly attractive nu- ever, most other species rely entirely on intrinsic
T
Medical Research Council Laboratory of Molecular Biology,
trient source for potential parasites and self-defense for protection, which in some cases Division of Protein and Nucleic Acid Chemistry, Francis Crick
pathogens. All organisms must therefore has reached an astonishing level of complex- Avenue, Cambridge CB2 0QH, UK. 2Department of Microbial
Pathogenesis, Boyer Centre for Molecular Medicine, Yale Uni-
have developed the ability to defend against such ity. In archaea and bacteria, for example, even versity School of Medicine, New Haven, CT 06510, USA.
threats early during evolution (1). In metazoans, adaptive forms of resistance—long considered *Corresponding author. E-mail: randow@mrc-lmb.cam.ac.uk
specialized immune cells stimulate innate immu- the hallmark of vertebrates—contribute to cell- (F.R.); john.macmicking@yale.edu (J.D.M.); lcj@mrc-lmb.cam.
nity and, in vertebrates, adaptive immunity; how- autonomous immunity, as exemplified by the ac.uk (L.C.J.)
spicuously out of place. In mam- TRIM28 gic machinery to engulf host protein
TRANSCRIPTION TRIM22
mals, compartmentalized Toll-like aggregates and damaged organelles
receptors (TLRs) detect pathogens (6, 18).
that reside within this network (10). Autophagy efficiently restricts the
TLRs 3, 7, 8, and 9 are delivered by NUCLEAR EXPORT
subpopulation of vesicle-inhabiting
endoplasmic reticulum (ER) chaper- CRM1 bacteria that, by damaging the lim-
ZAP
ones plus sorting adaptors to endo- ASSEMBLY iting membrane of their vacuole,
somes and lysosomes for sensing CNP become exposed to the cytosol, for
foreign nucleic acids (10). These example, Mycobacterium tuberculosis
luminal TLRs remain inactive un- BUDDING Tetherin and Salmonella Typhimurium (18).
til their ectodomain is cleaved by Professional cytosol-dwelling patho-
proteases in the endolysosomal sys- gens like Listeria monocytogenes
tem, a possible safeguard against ac- avoid such attacks [see review in
tivation by self RNA and DNA (10). this issue (40)]. Phagophore recruit-
Their strategic location also enables ment to bacteria depends on three
Fig. 3. Multilayered defenses synergistically inhibit infection and
sampling of genetic material exposed pathogen replication. To infect cells and complete their life cycle, retro- nonredundant cargo receptors, i.e.,
after endolysosomal degradation. Tar- viruses, such as HIV-1, must pass through multiple compartment borders and NDP52 (41), p62 (42), and optineurin
geting PRRs to compartments that access distinct cellular compartments. Virions must recruit and retask cellular (43). Their bacteria-associated eat-me
harbor their respective nucleic acid cofactors to negotiate their way through the cell and to replicate successfully. signals arise from (i) active ubiquitin
ligands thus enables immune sur- Meanwhile, antiviral factors adapted to specific cellular microenvironments deposition by host cells around sus-
veillance of its enclosed cargo. target and inhibit specific steps of the viral life cycle. At each stage, only a ceptible bacteria, for example, by the
Besides DNA and RNA, struc- fraction of virions are successful, which provides a highly synergistic defense E3 ligase LRSAM1 (6, 18, 44); (ii)
tural PAMPs also elicit strong cel- system capable of inhibiting even quickly evolving pathogens. LEDGF, PC4 and cytosolic exposure of intravesicular
lular self-defenses. Translocation of SFRS1 interacting protein–1; ZAP, zinc finger CCCH-type antiviral protein–1. glycans upon bacterial damage of the
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