Yersinia Type III Secretion System Master Regulator LcrF

Abstract

c Many Gram-negative pathogens express a type III secretion (T3SS) system to enable growth and survival within a host. The three human-pathogenic Yersinia species, Y. pestis, Y. pseudotuberculosis, and Y. enterocolitica, encode the Ysc T3SS, whose expression is controlled by an AraC-like master regulator called LcrF. In this review, we discuss LcrF structure and function as well as the environmental cues and pathways known to regulate LcrF expression. Similarities and differences in binding motifs and modes of action between LcrF and the Pseudomonas aeruginosa homolog ExsA are summarized. In addition, we present a new bioinformatics analysis that identifies putative LcrF binding sites within Yersinia target gene promoters. There are three Yersinia species pathogenic to humans. Y. pestis is the causative agent of bubonic and pneumonic plague and is transmitted through a flea vector or through airborne transmission from one mammalian host to another (1). In contrast, the enteropathogenic Yersinia species Y. enterocolitica and Y. pseudotuberculosis grow in the environment but can be transmitted to mammalian hosts through ingestion of contaminated food or water (1). Y. enterocolitica and Y. pseudotuberculosis cause typically self-limiting mesenteric lymphadenitis or gastroenteritis in otherwise healthy individuals but can cause a serious blood-borne infection in people with iron overload disorders such as hereditary hemochromatosis (2). In addition, sequelae following enteropathogenic Yersinia infection, such as erythema nodosum and reactive arthritis, have also been reported (3-5).Human-pathogenic Yersinia species share a virulence plasmid, called pCD1 in Y. pestis and pYV in enteropathogenic yersiniae, encoding the Ysc type III secretion system (T3SS) essential for causing disease (6). These 70-kb plasmids carry dozens of T3SS structural genes and encode five or six T3SS effector proteins called Yops and their dedicated chaperones, as well as genes encoding proteins involved in regulating expression and function of the T3SS. One of these regulatory proteins, LcrF, serves as the Yersinia T3SS master regulator, controlling transcription of a large number of plasmid-borne genes. Several environmental cues influence expression of LcrF itself, possibly enabling Yersinia to control T3SS expression during transitions from one niche to another. Recent reviews have highlighted important advances in our understanding of T3SS structure and modulation of the innate immune response by T3SS effector proteins (7). In this review, we focus on factors controlling LcrF expression, the target genes LcrF regulates, and how LcrF activity influences Yersinia pathogenesis. LcrF HISTORY, STRUCTURE, AND FUNCTIONIt has long been appreciated that human-pathogenic Yersinia carrying T3SS genes requires millimolar concentrations of calcium to grow at 37°C, and this phenomenon was termed the low-calcium response, or Lcr (8, 9). The absence of calcium, in combination with a shift to 37°C, triggers secretion of T3SS effector proteins, mimicking t...

Iron availability and oxygen tension regulate the Yersinia Ysc type III secretion system to enable disseminated infection

“…LcrF expression is upregulated at 37˚C, mammalian host body temperature, and upon calcium depletion, which is thought to mimic contact with host cells [33,[35][36][37][38]. LcrF thermal control is mediated by host temperature dependent degradation of the negative regulator YmoA to activate lcrF transcription at mammalian body temperature and an RNA thermometer that represses LcrF translation at environmental temperatures [32,35,38,39]. A recent study showed that low calcium or host cell contact lead to secretion of a T3SS cargo protein and regulator, YopD, that ultimately affects lcrF mRNA stability [40].…”

“…The region containing the IscR binding site upstream of lcrF is 100% identical between Y. pseudotuberculosis and Y. pestis [32]. Therefore, we sought to determine if T3SS activity in Y. pestis also required IscR despite the difference in life cycles carried out by enteropathogenic Yersinia compared to Y. pestis.…”

Temperature Control of psaA Expression by PsaE and PsaF in Yersinia pestis

“…Our finding that the 5′ UTR of psaE regulates translation initiation of psaE in response to a temperature upshift resembles the recently described mechanism regulating temperature-dependent synthesis of LcrF, a major virulence regulator of the type III secretion system (T3SS) in Yersinia spp. ( 37 , 41 ). Similar to our findings with PsaE/PsaF, the synthesis of LcrF in Y. pestis is significantly increased at high temperature and corresponds with the expression of type III secretion system (T3SS) genes regulated by LcrF ( 42 , 43 ).…”

Type VI Secretion Systems Present New Insights on Pathogenic Yersinia

“…Despite differences in pathogenesis, these virulent Yersinia species have several common virulence factors, including the 70-kb virulence plasmid (pCD1 in Y. pestis and pYV in enteropathogenic Yersinia ) and the yersiniabactin (Ybt) system (Brubaker, 1991 ; Heesemann et al, 1993 ; Cornelis et al, 1998 ). The 70-kb plasmid contains dozens of genes encoding structural components of a type III secretion system (T3SS), and also encodes several T3SS effector proteins called Yersinia outer proteins (Yops) and their dedicated chaperones to subvert the innate immune system of the hosts (Bliska et al, 2013 ; Schwiesow et al, 2015 ). Since enzymes/toxins/effectors delivered by secretion systems play a crucial role in the interaction between pathogens and their hosts or competitors, the various types of secretion systems attract interest in the research on pathogenic bacteria.…”