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Most secretory proteins are folded and modified in the endoplasmic reticulum (ER); however, protein folding is error-prone, resulting in toxic protein aggregation and cause ER stress. Irreversibly misfolded proteins are subjected to ER-associated degradation (ERAD), modified by ubiquitination, and degraded by the 26S proteasome. The yeast ERAD ubiquitin ligase Hrd1p and multispanning membrane protein Der1p are involved in ubiquitination and transportation of the folding-defective proteins. Here, we performed functional characterization of MoHrd1 and MoDer1 and revealed that both of them are localized to the ER and are pivotal for ERAD substrate degradation and the ER stress response. MoHrd1 and MoDer1 are involved in hyphal growth, asexual reproduction, infection-related morphogenesis, protein secretion and pathogenicity of M. oryzae. Importantly, MoHrd1 and MoDer1 mediated conidial autophagic cell death and subsequent septin ring assembly at the appressorium pore, leading to abnormal appressorium development and loss of pathogenicity. In addition, deletion of MoHrd1 and MoDer1 activated the basal unfolded protein response (UPR) and autophagy, suggesting that crosstalk between ERAD and two other closely related mechanisms in ER quality control system (UPR and autophagy) governs the ER stress response. Our study indicates the importance of ERAD function in fungal development and pathogenesis of M. oryzae.

The endoplasmic reticulum (ER) is the entry portal of the conventional secretory pathway where the newly synthesized polypeptides fold, modify, and assemble. The ER responses to the unfolded proteins in its lumen (ER stress) by triggering intracellular signal transduction pathways include the ER-associated degradation (ERAD) pathway and the unfolded protein response (UPR) pathway. In yeast and mammals, the ubiquitin ligase Hrd1 is indispensable for the ERAD pathway, and also Hrd1-mediated ERAD pathway plays a crucial role in maintaining homeostasis and metabolism of human beings. However, the underlying physiological roles and regulatory mechanism of the Hrd1-involved ERAD pathway in the plant pathogenic fungi are still unclear. Here, we identified the Hrd1 orthologous proteins from 9 different fungi and noticed that these Hrd1 orthologs are conserved. Through identification of MoHrd1 putative interacting proteins by co-immunoprecipitation assays and enrichment analysis, we found that MoHrd1 is involved in the secretory pathway, energy synthesis, and metabolism. Taken together, our results suggest that MoHrd1 is conserved among fungi and play an important role in cellular metabolism and infection-related development. Our finding helps uncover the mechanism of Hrd1-involved ERAD pathway in fungi and sheds a new light to understand the pathogenic mechanism of Magnaporthe oryzae.

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