Sec62 Inhibitors

Chemical inhibitors of Sec62 can disrupt its function through various mechanisms related to the protein synthesis and translocation processes of the endoplasmic reticulum (ER). Thapsigargin and Cyclopiazonic Acid are two such inhibitors that target the sarcoplasmic/endoplasmic reticulum Ca2+ ATPases (SERCA), leading to a dysregulation of calcium homeostasis. This increase in cytosolic calcium concentration can adversely impact calcium-dependent processes, including those that Sec62 relies on for the post-translational translocation into the ER. Similarly, Gossypol induces ER stress, which in turn can impair the functioning of Sec62 by overwhelming its protein translocation mechanism. Salubrinal, on the other hand, inhibits the dephosphorylation of eIF2α, resulting in a reduction of global protein synthesis, thereby limiting the availability of nascent polypeptides for Sec62 to translocate into the ER lumen.

Eeyarestatin I and its derivative, EerI, disrupt the ER-associated degradation (ERAD) pathway by targeting the p97 ATPase and associated deubiquitination activities. Since Sec62 plays a role in the ERAD pathway by translocating misfolded proteins from the ER back into the cytosol, its function is compromised when the ERAD pathway is inhibited. Brefeldin A also hinders Sec62 activity by disrupting transport between the ER and the Golgi apparatus. This is achieved through the inhibition of ADP-ribosylation factor (ARF), which is essential for maintaining the secretory pathway that Sec62 partially depends on. Suberoylanilide Hydroxamic Acid (SAHA) exacerbates this effect by increasing protein misfolding within the ER, which can indirectly inhibit the function of Sec62 by adding stress to the protein translocation process. Lastly, Ceapin-A7 targets ATF6, which is involved in the ER stress response, and by inhibiting this transcription factor, it can reduce the role of Sec62 in managing ER stress. Tunicamycin's mechanism of blocking N-linked glycosylation also contributes to a disruption of Sec62 function, as glycosylation status can affect protein translocation processes that Sec62 is involved with. MG-132 compounds the effects of these inhibitors by causing the accumulation of polyubiquitinated proteins, leading to sustained ER stress and an overload on the system that Sec62 is designed to manage.