Kallikrein-related peptidases

Lundwall, Å.; Brattsand, Maria

doi:10.1007/s00018-008-8024-3

Cited by 131 publications

(117 citation statements)

References 139 publications

(178 reference statements)

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“…S3 in the supplemental material) and is therefore unlikely to be the primary SEM1(86-107)-cleaving protease. Given that degradation of SEM1(86-107) in semen is inhibited in the presence of a serine protease inhibitor, it is likely that the responsible protease(s) is another serine protease(s), such as the numerous kallikrein-related peptidases expressed in human semen (28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

Liquefaction of Semen Generates and Later Degrades a Conserved Semenogelin Peptide That Enhances HIV Infection

Roan

Liu

Usmani

et al. 2014

J Virol

106

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Semen enhances HIV infection in vitro, but how long it retains this activity has not been carefully examined. Immediately postejaculation, semen exists as a semisolid coagulum, which then converts to a more liquid form in a process termed liquefaction. We demonstrate that early during liquefaction, semen exhibits maximal HIV-enhancing activity that gradually declines upon further incubation. The decline in HIV-enhancing activity parallels the degradation of peptide fragments derived from the semenogelins (SEMs), the major components of the coagulum that are cleaved in a site-specific and progressive manner upon initiation of liquefaction. Because amyloid fibrils generated from SEM fragments were recently demonstrated to enhance HIV infection, we set out to determine whether any of the liquefaction-generated SEM fragments associate with the presence of HIVenhancing activity. We identify SEM1 from amino acids 86 to 107 [SEM1(86-107)] to be a short, cationic, amyloidogenic SEM peptide that is generated early in the process of liquefaction but that, conversely, is lost during prolonged liquefaction due to the activity of serine proteases. Synthetic SEM1(86-107) amyloids directly bind HIV-1 virions and are sufficient to enhance HIV infection of permissive cells. Furthermore, endogenous seminal levels of SEM1(86-107) correlate with donor-dependent variations in viral enhancement activity, and antibodies generated against SEM1(86-107) recognize endogenous amyloids in human semen. The amyloidogenic potential of SEM1(86-107) and its virus-enhancing properties are conserved among great apes, suggesting an evolutionarily conserved function. These studies identify SEM1(86-107) to be a key, HIV-enhancing amyloid species in human semen and underscore the dynamic nature of semen's HIV-enhancing activity. IMPORTANCESemen, the most common vehicle for HIV transmission, enhances HIV infection in vitro, but how long it retains this activity has not been investigated. Semen naturally undergoes physiological changes over time, whereby it converts from a gel-like consistency to a more liquid form. This process, termed liquefaction, is characterized at the molecular level by site-specific and progressive cleavage of SEMs, the major components of the coagulum, by seminal proteases. We demonstrate that the HIV-enhancing activity of semen gradually decreases over the course of extended liquefaction and identify a naturally occurring semenogelin-derived fragment, SEM1(86-107), whose levels correlate with virus-enhancing activity over the course of liquefaction. SEM1(86-107) amyloids are naturally present in semen, and synthetic SEM1(86-107) fibrils bind virions and are sufficient to enhance HIV infection. Therefore, by characterizing dynamic changes in the HIV-enhancing activity of semen during extended liquefaction, we identified SEM1(86-107) to be a key virus-enhancing component of human semen. Human semen is a complex biological fluid that begins as a gelatinous structure and, over time, undergoes regulated changes in consistenc...

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Section: Discussionmentioning

confidence: 99%

Liquefaction of Semen Generates and Later Degrades a Conserved Semenogelin Peptide That Enhances HIV Infection

Roan

Liu

Usmani

et al. 2014

J Virol

106

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“…Human tissue kallikrein-related peptidases (KLKs) 2 belong to a subgroup of secreted serine proteases within the S1 family of clan SA. So far, 15 members of the family (KLK1-15) have been identified and found expressed in a large number of tissues and cell populations (1).…”

mentioning

confidence: 99%

Kallikrein-related Peptidase 12 Hydrolyzes Matricellular Proteins of the CCN Family and Modifies Interactions of CCN1 and CCN5 with Growth Factors

Guillon-Munos

Οικονομοπούλου

Michel

et al. 2011

Journal of Biological Chemistry

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Kallikrein-related peptidases (KLKs) are an emerging group of secreted serine proteases involved in several physiological and pathological processes. We used a degradomic approach to identify potential substrates of KLK12. MDA-MB-231 cells were treated either with KLK12 or vehicle control, and the proteome of the overlying medium was analyzed by mass spectrometry. CCN1 (cyr61, ctgf, nov) was among the proteins released by the KLK12-treated cells, suggesting that KLK12 might be responsible for the shedding of this protein from the cell surface. Fragmentation of CCN1 by KLK12 was further confirmed in vitro, and the main cleavage site was localized in the hinge region between the first and second half of the recombinant protein. KLK12 can target all six members of the CCN family at different proteolytic sites. Limited proteolysis of CCNs (cyr61, ctgf, nov) was also observed in the presence of other members of the KLK family, such as KLK1, KLK5, and KLK14, whereas KLK6, KLK11, and KLK13 were unable to fragment CCNs. Because KLK12 seems to have a role in angiogenesis, we investigated the relations between KLK12, CCNs, and several factors known to be involved in angiogenesis. Solid phase binding assays showed that fragmentation of CCN1 or CCN5 by KLK12 prevents VEGF 165 binding, whereas it also triggers the release of intact VEGF and BMP2 from the CCN complexes. The KLK12-mediated release of TGF-␤1 and FGF-2, either as intact or truncated forms, was found to be concentration-dependent. These findings suggest that KLK12 may indirectly regulate the bioavailability and activity of several growth factors through processing of their CCN binding partners.

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“…To date, SC serine protease activity is attributed to human tissue KLKs (Borgono et al 2007). At least eight KLKs have been reported to be expressed in healthy skin, of which KLK5, KLK7, KLK8, and KLK14 seem to be the most important (reviewed in (Lundwall and Brattsand 2008)). Their putative function has been extensively studied (reviewed in (Eissa and Diamandis 2008;Lundwall and Brattsand 2008).…”

Section: Kallikrein-related Peptidasesmentioning

confidence: 99%

“…At least eight KLKs have been reported to be expressed in healthy skin, of which KLK5, KLK7, KLK8, and KLK14 seem to be the most important (reviewed in (Lundwall and Brattsand 2008)). Their putative function has been extensively studied (reviewed in (Eissa and Diamandis 2008;Lundwall and Brattsand 2008). A wealth of literature revealed proteolytic function of the two serine proteases, KLK5 and KLK7, in SC.…”

Section: Kallikrein-related Peptidasesmentioning

confidence: 99%