proteins involved in heterokaryon incompatibility (Smith et al. 2000; Zhao et al. 2015) and
found to show a remote homology to plant and
mammalian TIR domains (Dyrka et al. 2014).
The C-terminal domain of HET-e is a WDrepeat domain. het-e and het-c both exist as
numerous alleles, and incompatibility is triggered when a specific allele of het-e interacts
with a specific allele of het-c (Bastiaans et al.
2014; Saupe et al. 1995b). het-c encodes a glycolipid transfer protein that is conserved in plants
and mammals and involved in transfer of glycolipids between cellular compartments. Recognition of proteins encoded by het-c alleles
is mediated by the C-terminal WD-repeat
domain. het-e presents many paralogs in
Podospora, two of which are also het-genes.
het-d defines a second incompatibility system
in interaction with the het-c locus (Espagne
et al. 2002), and Het-r defines an incompatibility system with a second gene termed het-v
which has not been molecularly characterized
at present (Chevanne et al. 2009). Two types of
het-r alleles have been described: het-R alleles
active in incompatibility and het-r alleles which
are inactive. het-R and het-r alleles differ by the
number of WD-repeats in their C-terminal
domain. Inactivity of het-r alleles results from
loss of repeats in the WD-repeat domain (Chevanne et al. 2009, 2010). NLRs are also involved,
although indirectly, in allelic incompatibility
systems in Podospora. The allelic het-s/het-S
prion-dependent
incompatibility
system
derives from an NLR-based signaling pathway
controlled by a protein termed NWD2, which is
encoded by a gene belonging to the same gene
family as het-d, het-e, and het-r. NWD2 displays
a NACHT domain and WD-repeats, but unlike
the above described examples of incompatibility systems, this NLR is not required for the
incompatibility reaction per se as will be developed in a later section (Daskalov et al. 2015b).
N. crassa is a major model system for the
study of incompatibility, and incompatibility
loci have been genetically identified in that species, and several of the corresponding genes
have been cloned and functionally characterized (Daskalov et al. 2017; Garnjobst and Wilson 1956). In addition, in that species, a
programmed cell death reaction has been
found to occur after fusion of germ tubes
from germinating conidia of unlike genotype
(Heller et al. 2018). This programmed germling
death is conceptually analogous to heterokaryon incompatibility although it was not
identified using the classical assays employed
to characterize het genes, namely, confrontation tests (barrage tests) or forced heterokaryons. Germling death is regulated by a two
linked highly polymorphic loci with four haplotypes in N. crassa population samples (Heller
et al. 2018). More specifically, death is mediated
by non-allelic interactions between two linked
genes, plp-1 and sec-9. Plp-1 encodes an NLR
with a NB-ARC NOD domain, C-terminal TPRrepeats, and an N-terminal patatin-like phospholipase domain. sec-9 codes for a SNARE
protein involved in the membrane fusion process during exocytosis. Germling death is triggered by the physical interaction of PLP-1 and
SEC-9 and involves PLP-1 oligomerization.
Death is dependent on the predicted phospholipase activity of PLP-1 since a catalytic mutant
of PLP-1 fails to induce cell death but retains
the ability to recognize SEC-9. Remarkably, the
orthologs of these genes in Cryphonectria parasitica correspond to the vic2a and vic2b incompatibility genes and to the het-z incompatibility
locus of P. anserina, which also encodes plp-1
and sec-9 orthologs (Choi et al. 2012; Heller
et al. 2018). This gene pair thus functions in
non-self recognition and programmed cell
death control in three distinct species. Furthermore, functional studies in P. anserina suggest
that cell death induced by het-z during the
incompatibility reaction shares many mechanistic similarities with germling-regulated
death controlled by plp-1 in Neurospora. Notably, in both cases, recognition specificity is
mediated by the TPR domain, relies on a functional patatin-like domain, and is suppressed
by a mutation of the P-loop motif of the NOD
domain (Heller et al. 2018). The occurrence of
an allorecognition system involving the same
pair of genetic partners in these three species
could either be explained by a scenario of longterm conservation of the allorecognition function or by convergent evolution and reoccurring recruitment of these genes as allorecognition genes. Phylogenetic studies support a
126
A. Daskalov et al.
found to show a remote homology to plant and
mammalian TIR domains (Dyrka et al. 2014).
The C-terminal domain of HET-e is a WDrepeat domain. het-e and het-c both exist as
numerous alleles, and incompatibility is triggered when a specific allele of het-e interacts
with a specific allele of het-c (Bastiaans et al.
2014; Saupe et al. 1995b). het-c encodes a glycolipid transfer protein that is conserved in plants
and mammals and involved in transfer of glycolipids between cellular compartments. Recognition of proteins encoded by het-c alleles
is mediated by the C-terminal WD-repeat
domain. het-e presents many paralogs in
Podospora, two of which are also het-genes.
het-d defines a second incompatibility system
in interaction with the het-c locus (Espagne
et al. 2002), and Het-r defines an incompatibility system with a second gene termed het-v
which has not been molecularly characterized
at present (Chevanne et al. 2009). Two types of
het-r alleles have been described: het-R alleles
active in incompatibility and het-r alleles which
are inactive. het-R and het-r alleles differ by the
number of WD-repeats in their C-terminal
domain. Inactivity of het-r alleles results from
loss of repeats in the WD-repeat domain (Chevanne et al. 2009, 2010). NLRs are also involved,
although indirectly, in allelic incompatibility
systems in Podospora. The allelic het-s/het-S
prion-dependent
incompatibility
system
derives from an NLR-based signaling pathway
controlled by a protein termed NWD2, which is
encoded by a gene belonging to the same gene
family as het-d, het-e, and het-r. NWD2 displays
a NACHT domain and WD-repeats, but unlike
the above described examples of incompatibility systems, this NLR is not required for the
incompatibility reaction per se as will be developed in a later section (Daskalov et al. 2015b).
N. crassa is a major model system for the
study of incompatibility, and incompatibility
loci have been genetically identified in that species, and several of the corresponding genes
have been cloned and functionally characterized (Daskalov et al. 2017; Garnjobst and Wilson 1956). In addition, in that species, a
programmed cell death reaction has been
found to occur after fusion of germ tubes
from germinating conidia of unlike genotype
(Heller et al. 2018). This programmed germling
death is conceptually analogous to heterokaryon incompatibility although it was not
identified using the classical assays employed
to characterize het genes, namely, confrontation tests (barrage tests) or forced heterokaryons. Germling death is regulated by a two
linked highly polymorphic loci with four haplotypes in N. crassa population samples (Heller
et al. 2018). More specifically, death is mediated
by non-allelic interactions between two linked
genes, plp-1 and sec-9. Plp-1 encodes an NLR
with a NB-ARC NOD domain, C-terminal TPRrepeats, and an N-terminal patatin-like phospholipase domain. sec-9 codes for a SNARE
protein involved in the membrane fusion process during exocytosis. Germling death is triggered by the physical interaction of PLP-1 and
SEC-9 and involves PLP-1 oligomerization.
Death is dependent on the predicted phospholipase activity of PLP-1 since a catalytic mutant
of PLP-1 fails to induce cell death but retains
the ability to recognize SEC-9. Remarkably, the
orthologs of these genes in Cryphonectria parasitica correspond to the vic2a and vic2b incompatibility genes and to the het-z incompatibility
locus of P. anserina, which also encodes plp-1
and sec-9 orthologs (Choi et al. 2012; Heller
et al. 2018). This gene pair thus functions in
non-self recognition and programmed cell
death control in three distinct species. Furthermore, functional studies in P. anserina suggest
that cell death induced by het-z during the
incompatibility reaction shares many mechanistic similarities with germling-regulated
death controlled by plp-1 in Neurospora. Notably, in both cases, recognition specificity is
mediated by the TPR domain, relies on a functional patatin-like domain, and is suppressed
by a mutation of the P-loop motif of the NOD
domain (Heller et al. 2018). The occurrence of
an allorecognition system involving the same
pair of genetic partners in these three species
could either be explained by a scenario of longterm conservation of the allorecognition function or by convergent evolution and reoccurring recruitment of these genes as allorecognition genes. Phylogenetic studies support a
126
A. Daskalov et al.