Degenerative mechanisms
The second class of constitutive innate immune mechanisms functions through the degradation of danger molecules and elimination of unwanted cells. This class of mechanisms includes autophagy, phagocytosis, proteasomal degradation and nucleases (Table 1). Collectively, degenerative programmes function to continually limit danger signals, allowing for the rapid elimination of unwanted molecules without the activation of energy-consuming amplificative induced immune responses.
degradation 분해
elimination 제거
Collectively 집단적으로
continually 잇달아서
activation 활성화
amplificative 증폭
Autophagy and phagocytosis.
Autophagy and phagocytosis execute the digestion of intracellular and extracellular microorganisms, respectively, through membrane encapsulation followed by chemical and enzymatic degradation.
execute 실행하다
respectively 각각
encapsulation 캡슐화
enzymatic 효소의
Pathogens are shunted into these pathways through the recognition of polyubiquitin chains or glycans inside damaged vacuoles in the case of autophagy, and through complement coating of microorganisms in the case of phagocytosis.
Pathogen 병원균
shunt 이동시키다
vacuole 액포
In the case of autophagy, a large number of ubiquitin E3 ligases have been identified that coat viral and bacterial surfaces with ubiquitin, thus targeting microorganisms for loading into autophagosomes through interaction with the autophagosome-associated protein LC3 (also known as MAP1ALC3) (Fig. 4b).
autophagosome 자가포식소체
interaction 상호작용
처음에 알려진 기능은, 유비퀴틴이 다른 단백질에 결합함으로써 단백질의 분해를 촉진하는 것이었다...
b| Blockade of viral and bacterial replication by autophagy. Various ubiquitin E3 ligases (such as SMURF1, LRSAM1 and TRIM23) and ubiquitin-binding proteins (such as p62, optineurin and NDP52) have been identified to conjugate ubiquitin to microbial surfaces, which targets them for loading into autophagosomes. Also, cytosolic exposure of glycans by pathogen-damaged vesicles can be recognized by galectin 8 for targeting to autophagosomes
This targeting mechanism involves E3 ligases, including SMURF1 and LRSAM1 (refs), as well as the ubiquitin-binding selective autophagy receptors p62 (also known as SQSTM1), optineurin and NDP52 (also known as CALCOCO2). An alternative mechanism for sensing of vesicle-damaging pathogens has been identified that involves damaged vesicles exposing glycans in the cytoplasm for sensing by galactin 8, which links to autophagy via NDP52 .
vesicle 소낭
exposing 노출하는
via 통하여
This triggers phagophore formation in the vicinity of cytosolic bacteria. Autophagy has important roles in the control of infection. For example, defective autophagy leads to increased susceptibility to infection with Sindbis virus in mice. In addition, stimulation of autophagy in primary human macrophages mediated protection against M. tuberculosis infection.
triggers 촉발시키다
vicinity 부근
defective 결함이 있는
susceptibility 민감성
stimulation 자극
mediated 간접
protection 보호
However, mice defective in autophagy do not have impaired antimycobacterial defence in vivo, which indicates that the precise role of autophagy requires further investigation. Third, herpes simplex virus type 1 specifically interferes with autophagy, which is essential for neuropathogenicity of the virus.
Complement-mediated phagocytosis involves specific recognition of complement components bound to the surface of microorganisms by the corresponding complement receptors on phagocytes. Activation of the complement system, for example after sensing of glycans by the lectin pathway, leads to the formation of C3 convertase, eventually generating C3b, which binds to complement receptors, thus inducing phagocytosis.
corresponding 해당하는
eventually 결국
generate 발생시키다
Mice devoid of the lectin-based complement pathway have increased susceptibility to Staphylococcus aureus infection and impaired bacterial phagocytosis. Furthermore, several bacteria, including Streptococcus pyogenes, inhibit complement-mediated phagocytosis.
A third degenerative mechanism for the degradation of membrane-encapsulated extracellular material is LC3-associated phagocytosis (LAP), which uses components from both the phagocytosis and autophagy pathways. LAP is involved in the clearance of extracellular pathogens and dead cells, and LAP-deficient mice fail to clear Aspergillus fumigatus infection. Thus, autophagy, phagocytosis and LAP are important systems for immediate host defence.
degradation 저하
encapsulated 캡슐에 넣어진
clearance 없애기
Proteasomal degradation.
The proteasome is a cytoplasmic protein complex that degrades proteins by proteolysis. Proteins to be degraded are tagged by K48-linked polyubiquitylation, attracted to the proteasome, unfolded into polypeptides and then degraded. The proteasomal degradation pathway also contributes to immediate defence against infecting pathogens. For example, viruses can be detected by the ubiquitin E3 ligase TRIM21 through binding to antibody-bound viral capsids, which links to downstream proteasomal degradation. This process is involved in the elimination of infecting viral capsids from the cytoplasm and contributes to antiviral defence. Other studies have shown that the viral RNA-dependent RNA polymerase of turnip yellow mosaic virus is degraded by the ubiquitin– proteasome pathway to control infection. Proteasome activity also contributes to defence against many bacterial infections, including Yersinia spp. infections, and the ubiquitin–proteasome pathway is targeted by many viruses and bacteria to promote replication. For example, the human cytomegalovirus protein pUL25 inhibits proteasomal degradation of another viral protein, pUL26, to sustain the activity of a pUL26-mediated immune evasion mechanism. Collectively, these examples show that the conserved proteasome pathway is part of the constitutive immune defence repertoire.
Nucleases.
The cytoplasm contains RNAses and DNAses that eliminate unwanted nucleic acid species, including viral nucleic acids, and these enzymes can thereby contribute to sterilization of the cytoplasm. RNase L is a latent cytoplasmic exoribonuclease that is activated by 2′-5′ oligoadenylates produced by OASs. Although OASs are highly interferon inducible, they are also expressed at a basal level and hence induce basal RNase L activity116. Importantly, this activity has been suggested to contribute to basal restriction of coronaviruses in myeloid cells, and hence to protect other cell types from infection. TREX1 is a cytoplasmic exodeoxyribonuclease that eliminates DNA from the cytoplasm. Very few microorganisms have free DNA as part of their productive replication cycle, but exogenous and endogenous retroviruses have a cytoplasmic DNA step that is sensitive to degradation by TREX1. Consequently, Trex1–/– mice have increased levels of endogenous retroviral DNA in the cytoplasm, which indicates that TREX1 has a role in limiting retroviral infection and hence maintaining genome integrity.