A parallel model linking NLRs and allorecognition would consist in bypassing the recognition step for the activation of the NLR and
directly relying on the recruitment of its downstream executioner protein for the purposes of
conspecific discrimination. One such incompatibility system is the nwd2/het-S gene cluster.
In this example, mutations are proposed to
have occurred in the het-S gene, generating a
new allele termed het-s (small s) (Daskalov and
Saupe 2015). A critical mutation at position 33
in the HeLo domain, replacing a histidine residue with a proline residue (H33P), renders the
pore-forming protein unable to induce cell
death. As a consequence, the het-s allele
encodes a protein (the HET-s protein) that is
nearly identical to HET-S but only with the
prion-forming domain (PFD) remaining functional. This HET-s variant can exist as a soluble
monomer, in a state termed [Het-s*] (star
state), or as infectious aggregates (a prion
state), termed [Het-s]. The appearance of the
[Het-s] prion occurs sporadically at a low rate
and corresponds to a conformational transition
of the PFD of HET-s from unstructured—in the
monomeric form of the protein—to the specific
cross-b amyloid fold in the prion form. As the
HeLo domain of the protein is non-functional,
the prion state spreads in the colony, converting all HET-s monomers to adopt the amyloid
prion fold, so that strains of het-s genotype are
either prion-infected or prion-free. Only prioninfected [Het-s] strains trigger incompatibility
with strains of the het-S genotype. The cell
death reaction occurs when the amyloid death
fold carried by the [Het-s] prion templates the
PFD of the HET-S allelic variant, with a functional cytotoxic HeLo domain. Thus, the [Hets] prion plays an analogous role to an activated
NWD2, serving as a cell death trigger for HETS. The het-S gene has been co-opted in the hetS/het-s incompatibility system, which likely
operates only in Podospora, while the nwd2/
het-S gene cluster is conserved in various
other ascomycetes.
One way to frame fungal incompatibility is
to consider it with an autoimmune reaction,
analogous to what has been described as hybrid
necrosis in plants (Bomblies et al. 2007; Bomblies and Weigel 2007). Hybrid incompatibilities in plants are post-mating genetic
incompatibilities, characterized by dwarfism
and tissue necrosis of the F1 offspring between
genetically distinct parents. The phenomenon
has been consistently linked to innate immunity genes in plants and notably R (resistance)
genes, encoding the repertoire of plant NLRs
(Chae et al. 2014). One striking example of
plant autoimmunity is a lesion-mimicking
mutant of Arabidopsis thaliana—acd11 (accelerated cell death 11). Autoimmunity is caused
by a mutation in the ACD11 gene, which is a
homolog of het-c, the allorecognition determinant from P. anserina (Brodersen et al. 2002).
Remarkably, the autoimmune necrotic phenotype is dependent on an NLR receptor encoded
by the gene LAZ5 (Palma et al. 2010). While this
situation is reminiscent of the het-e/het-c and
het-d/het-c incompatibility systems in Podospora, where inappropriate NLR activation may
be caused by disruption/perturbation of the
“guardian-guardee” pair, other autoimmune
reactions in plants seem to implicate different
mechanisms. This is true, for example, for the
hybrid necrosis triggered by co-expression of
DM1 (DANGEROUS MIX 1) and DM2d, two
distinct NLR proteins, an incompatibility
mechanism not yet encountered in fungi
(Tran et al. 2017).
Hybrid necrosis in plants and heterokaryon
incompatibility in fungi may thus represent
very similar phenomena, emerging from anomalous activation of genes evolving primarily to
mediate heterospecific non-self recognition and
detection of modified self. However, the adaptive value of the two phenomena is likely different. Notably, the fungal specific lifestyle, where
colony establishment relies on anastomosis,
occasionally between genetically distinct individuals, would integrate some of the sporadically emerging allorecognition systems to
prevent conspecific parasitism and the spread
of deleterious elements like mycoviruses. In
that regard, one could argue that some of the
co-opted NLRs are (re)utilized as immune
receptors.
6 NLR Function in Fungi as Revealed by the Study of Self/Non-self Recognition Systems
137
directly relying on the recruitment of its downstream executioner protein for the purposes of
conspecific discrimination. One such incompatibility system is the nwd2/het-S gene cluster.
In this example, mutations are proposed to
have occurred in the het-S gene, generating a
new allele termed het-s (small s) (Daskalov and
Saupe 2015). A critical mutation at position 33
in the HeLo domain, replacing a histidine residue with a proline residue (H33P), renders the
pore-forming protein unable to induce cell
death. As a consequence, the het-s allele
encodes a protein (the HET-s protein) that is
nearly identical to HET-S but only with the
prion-forming domain (PFD) remaining functional. This HET-s variant can exist as a soluble
monomer, in a state termed [Het-s*] (star
state), or as infectious aggregates (a prion
state), termed [Het-s]. The appearance of the
[Het-s] prion occurs sporadically at a low rate
and corresponds to a conformational transition
of the PFD of HET-s from unstructured—in the
monomeric form of the protein—to the specific
cross-b amyloid fold in the prion form. As the
HeLo domain of the protein is non-functional,
the prion state spreads in the colony, converting all HET-s monomers to adopt the amyloid
prion fold, so that strains of het-s genotype are
either prion-infected or prion-free. Only prioninfected [Het-s] strains trigger incompatibility
with strains of the het-S genotype. The cell
death reaction occurs when the amyloid death
fold carried by the [Het-s] prion templates the
PFD of the HET-S allelic variant, with a functional cytotoxic HeLo domain. Thus, the [Hets] prion plays an analogous role to an activated
NWD2, serving as a cell death trigger for HETS. The het-S gene has been co-opted in the hetS/het-s incompatibility system, which likely
operates only in Podospora, while the nwd2/
het-S gene cluster is conserved in various
other ascomycetes.
One way to frame fungal incompatibility is
to consider it with an autoimmune reaction,
analogous to what has been described as hybrid
necrosis in plants (Bomblies et al. 2007; Bomblies and Weigel 2007). Hybrid incompatibilities in plants are post-mating genetic
incompatibilities, characterized by dwarfism
and tissue necrosis of the F1 offspring between
genetically distinct parents. The phenomenon
has been consistently linked to innate immunity genes in plants and notably R (resistance)
genes, encoding the repertoire of plant NLRs
(Chae et al. 2014). One striking example of
plant autoimmunity is a lesion-mimicking
mutant of Arabidopsis thaliana—acd11 (accelerated cell death 11). Autoimmunity is caused
by a mutation in the ACD11 gene, which is a
homolog of het-c, the allorecognition determinant from P. anserina (Brodersen et al. 2002).
Remarkably, the autoimmune necrotic phenotype is dependent on an NLR receptor encoded
by the gene LAZ5 (Palma et al. 2010). While this
situation is reminiscent of the het-e/het-c and
het-d/het-c incompatibility systems in Podospora, where inappropriate NLR activation may
be caused by disruption/perturbation of the
“guardian-guardee” pair, other autoimmune
reactions in plants seem to implicate different
mechanisms. This is true, for example, for the
hybrid necrosis triggered by co-expression of
DM1 (DANGEROUS MIX 1) and DM2d, two
distinct NLR proteins, an incompatibility
mechanism not yet encountered in fungi
(Tran et al. 2017).
Hybrid necrosis in plants and heterokaryon
incompatibility in fungi may thus represent
very similar phenomena, emerging from anomalous activation of genes evolving primarily to
mediate heterospecific non-self recognition and
detection of modified self. However, the adaptive value of the two phenomena is likely different. Notably, the fungal specific lifestyle, where
colony establishment relies on anastomosis,
occasionally between genetically distinct individuals, would integrate some of the sporadically emerging allorecognition systems to
prevent conspecific parasitism and the spread
of deleterious elements like mycoviruses. In
that regard, one could argue that some of the
co-opted NLRs are (re)utilized as immune
receptors.
6 NLR Function in Fungi as Revealed by the Study of Self/Non-self Recognition Systems
137