Deletion of Herp facilitates degradation of cytosolic proteins

Although intracellular stresses are believed to be involved in the process of neurodegeneration, it is not fully understood how one stress/stress response affects another. Herp is an endoplasmic reticulum (ER)-located membrane protein proposed to function in ER-associated degradation (ERAD). Herp is strongly induced by ER stress but rapidly degraded by proteasome. To elucidate the effect of Herp expression on proteolytic stress caused by impairment of the ubiquitin-proteasome system (UPS), we utilized 293T Herp knockdown (KD) cells and F9 Herp knockout cells. Knockdown of Herp gene unexpectedly facilitated the degradation of Parkinson's disease-associated cytosolic proteins such as alpha-synuclein and its binding partner, synphilin-1, and improved cell viability during proteasomal inhibition. A similar tendency was observed in F9 Herp knockout cells transfected with synphilin-1. Herp temporarily bound to alpha-synuclein, synphilin-1 and the E3 ligase SIAH1a during proteolytic stress but not during ER stress. Furthermore, deletion of Herp enhanced the amount of ubiquitinated protein in the cytosol during proteasomal inhibition, although it did not affect the activity or expression of proteasome. These results suggest that ERAD molecule Herp may delay the degradation of cytosolic proteins at the ubiquitination step.