Nonself recognition during somatic growth is an essential and ubiquitous phenomenon in both prokaryotic and eukaryotic species. In filamentous fungi, nonself recognition is also important during vegetative growth. Hyphal fusion between genetically dissimilar individuals results in rejection of heterokaryon formation and in programmed cell death of the fusion compartment. In filamentous fungi, such as Neurospora crassa, nonself recognition and heterokaryon incompatibility (HI) are regulated by genetic differences at het loci. In N. crassa, mutations at the vib-1 locus suppress nonself recognition and HI mediated by genetic differences at het-c/pin-c, mat, and un-24/het-6. vib-1 is a homolog of Saccharomyces cerevisiae NDT80, which is a transcriptional activator of genes during meiosis. For this study, we determined that vib-1 encodes a nuclear protein and showed that VIB-1 localization varies during asexual reproduction and during HI. vib-1 is required for the expression of genes involved in nonself recognition and HI, including pin-c, tol, and het-6; all of these genes encode proteins containing a HET domain. vib-1 is also required for the production of downstream effectors associated with HI, including the production of extracellular proteases upon carbon and nitrogen starvation. Our data support a model in which mechanisms associated with starvation and nonself recognition/HI are interconnected. VIB-1 is a major regulator of responses to nitrogen and carbon starvation and is essential for the expression of genes involved in nonself recognition and death in N. crassa.Nonself recognition during somatic growth is an essential and ubiquitous phenomenon in both prokaryotic and eukaryotic species. In vertebrate species, self/nonself recognition relies on the major histocompatibility complex (MHC), which is an array of polymorphic genetic loci that generate proteins important in pathogen recognition and the activation of defense mechanisms (37). In filamentous fungi, nonself recognition is important during vegetative growth. Hyphal fusion between genetically dissimilar individuals results in rejection of heterokaryon formation and in programmed cell death of the fusion compartment (Fig. 1), an event analogous to nonself recognition following fusion in colonial marine invertebrates, such as Hydractinia and Botryllus (32, 73), and nonself recognition and death following fusion of plasmodia in the slime mold Physarum polycephalum (9). Nonself recognition during heterokaryon formation in filamentous fungi is regulated genetically by het loci (for heterokaryon incompatibility [HI]) (29,70,86). In the filamentous fungus Neurospora crassa, 11 het loci mediate nonself recognition and HI (28, 63); each het locus has two or three alternative allelic specificities. Since these het loci are effectively unlinked, the number of possible het genotypes within a segregating population is at least 2 11 genotypes, thus forming an effective barrier to heterokaryon formation between genetically different isolates. HI in filamentous fungi...