Heat shock proteins: linking danger and pathogen recognition

Osterloh, Anke; Breloer, Minka

doi:10.1007/s00430-007-0055-0

Cited by 119 publications

(97 citation statements)

References 66 publications

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“…The requirement for mtHsp70 in granzyme mitochondrial import is less surprising as GA and GB have been shown to interact strongly with cytosolic Hsp27, Hsp70 and Hsp90. [69][70][71] SSC1-3 allele presents a G56S mutation in the mtHsp70 ATPase domain, 72 indicating that GB might cross the inner mitochondrial membrane in a forceful manner. Moreover SSC1-2 yeast strain carries an allele of mtHsp70 that poorly interact with Tim44 at 37°C.…”

Section: Discussionmentioning

confidence: 99%

Granzyme B enters the mitochondria in a Sam50-, Tim22- and mtHsp70-dependent manner to induce apoptosis

et al. 2017

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We have found that granzyme B (GB)-induced apoptosis also requires reactive oxygen species resulting from the alteration of mitochondrial complex I. How GB, which does not possess a mitochondrial targeting sequence, enter this organelle is unknown. We show that GB enters the mitochondria independently of the translocase of the outer mitochondrial membrane complex, but requires instead Sam50, the central subunit of the sorting and assembly machinery that integrates outer membrane β-barrel proteins. Moreover, GB breaches the inner membrane through Tim22, the metabolite carrier translocase pore, in a mitochondrial heat-shock protein 70 (mtHsp70)-dependent manner. Granzyme A (GA) and caspase-3 use a similar route to the mitochondria. Finally, preventing GB from entering the mitochondria either by mutating lysine 243 and arginine 244 or depleting Sam50 renders cells more resistant to GB-mediated reactive oxygen species and cell death. Similarly, Sam50 depletion protects cells from GA-, GM-and caspase-3-mediated cell death. Therefore, cytotoxic molecules enter the mitochondria to induce efficiently cell death through a noncanonical Sam50-, Tim22-and mtHsp70-dependent import pathway.Cytotoxic lymphocytes eradicate pathogen-infected or transformed cells mainly through the cytotoxic granule pathway. [1][2][3][4] Among the five human granzymes (A, B, H, K and M), granzyme B (GB) triggers cell death in both a caspasedependent and caspase-independent manner, although human and mouse GB differ in their requirement for caspase activation. 5-10 GB-induced cell death also involves Bid/Bax/ Bak-mediated mitochondrial outer membrane permeabilization for the release of the apoptogenic factors cytochrome c, Smac/Diablo, Endo G, HtrA2 and AIF. 1,9-17 We have recently reported that mitochondrial reactive oxygen species (ROS) have a critical role in GB pathway by amplifying apoptogenic factor release, oligonucleosomal DNA fragmentation and lysosomal membrane rupture. 18 Mitochondrial ROS resulted from GB-mediated cleavage of NDUFV1, NDUFS1 and NDUFS2, three subunits of mitochondrial complex I. 18 How GB that does not possess a mitochondrial targeting sequence enters the mitochondria is not known. The mitochondrial nucleoid encodes only for 13 structural proteins, while the rest of the mitochondrial proteome is nuclear-encoded and transported to the mitochondria through a sophisticated protein import machinery. [19][20][21][22][23][24][25][26][27][28] The translocase of the outer mitochondrial membrane (TOM), the entry gate to the mitochondria, 20 passes on the cargos to the sorting and assembly machinery (SAM) complex, to the mitochondrial intermembrane space assembly (MIA) complex and to the translocases of the inner mitochondrial membrane TIM22 or TIM23 complexes for delivery to the outer membrane, the intermembrane space, the inner membrane or the matrix, respectively. [19][20][21][22]25,26,28 Unexpectedly, we found that GB mitochondrial entry is independent of the TOM-TIM23 complexes, but requires instead the Sam50 and Tim22 chann...

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Section: Discussionmentioning

confidence: 99%

Granzyme B enters the mitochondria in a Sam50-, Tim22- and mtHsp70-dependent manner to induce apoptosis

et al. 2017

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“…93 A large body of evidence implicates heat-shock protein 70 (HSP70) as a potential danger signal and it is interesting to note that HSP70 has been shown to mediate the uptake of granzyme B in a perforin-independent manner. 94 It is therefore intriguing to speculate that high levels circulating HSP70, released during situations of nonphysiological cell death such as chronic viral infection, may mediate the uptake of serum granzyme B by cells of the immune system and thus propagate the emerging proinflammatory properties of this protease. However, it is clear that investigations into the uptake of granzymes in noncytotoxic scenarios will require many more studies before a clearer picture begins to emerge.…”

Section: How Are Granzymes Released During Inflammation?mentioning

confidence: 99%

Granzymes in cancer and immunity

2010

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“…While it has been widely established that TLRs are the key mediators in the response to invading pathogens, there is a growing line of evidence suggesting that TLRs can be activated by endogenous "danger signals" released from the injured or necrotic cells. More particularly, TLR2 and TLR4 can interact with endogenous alarm signals such as heat shock proteins (Hsp60 and 70), extracellular breakdown product of hyaluron lipoproteins, etc., suggesting that TLRs may be involved in the regulation of inXammatory response following brain injuries [5,47,106] and neurodegeneration [99,105]. Recent studies demonstrated that TLRs, in particular TLR2 may be an important mediator of CNS ischemic injury [83,147].…”

Section: Tlrs Response To Ischemic Injury and Neurogenesismentioning

confidence: 99%

Inflammation, plasticity and real-time imaging after cerebral ischemia

2009

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With an incidence of approximately 350 in 100,000, stroke is the third leading cause of death and a major cause of disability in industrialized countries. At present, although progress has been made in understanding the molecular pathways that lead to ischemic cell death, the current clinical treatments remain poorly eVective. There is mounting evidence that inXammation plays an important role in cerebral ischemia. Experimentally and clinically, brain response to ischemic injury is associated with an acute and prolonged inXammatory process characterized by the activation of resident glial cells, production of inXammatory cytokines as well as leukocyte and monocyte inWltration in the brain, events that may contribute to ischemic brain injury and aVect brain recovery and plasticity. However, whether the post-ischemic inXammatory response is deleterious or beneWcial to brain recovery is presently a matter of debate and controversies. Here, we summarize the current knowledge on the molecular mechanisms underlying post-ischemic neuronal plasticity and the potential role of inXammation in regenerative processes and functional recovery after stroke. Furthermore, because of the dynamic nature of the brain inXammatory response, we highlight the importance of the development of novel experimental approaches such as real-time imaging. Finally, we discuss the novel transgenic reporter mice models that have allowed us to visualize and to analyze the processes such as neuroinXammation and neuronal repair from the ischemic brains of live animals.

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Heat shock proteins: linking danger and pathogen recognition

Cited by 119 publications

References 66 publications

Granzyme B enters the mitochondria in a Sam50-, Tim22- and mtHsp70-dependent manner to induce apoptosis

Granzyme B enters the mitochondria in a Sam50-, Tim22- and mtHsp70-dependent manner to induce apoptosis

Granzymes in cancer and immunity

Inflammation, plasticity and real-time imaging after cerebral ischemia

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