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Abstract In the face of a challenging climate STEM (Science, Technology, Engineering and Mathematics) higher education that is resistant to Diversity, Equity, and Inclusion efforts aimed to increase and retain students from historically excluded groups (HEGs), there is a critical need for a support structure to ensure students from HEGs continue to be recruited retained. The Biology Undergraduate and Master's Mentorship Program (BUMMP) embodies this commitment to fostering scientific identity, efficacy, and a sense of belonging for first‐generation and historically underserved undergraduate and master's students at UC San Diego. The mission of BUMMP is to cultivate a sense of belonging, instill confidence, and nurture a strong scientific identity amongst all its participants. At its core, the three pillars of BUMMP are (1) mentorship, (2) professional development, and (3) research. Quality mentorship is provided where students receive personal guidance from faculty, graduate students, postdocs, and industry leaders in navigating their career pathways. Complementing mentorship, BUMMP provides paid research opportunities and prioritizes professional development by offering workshops designed to enhance students' professional skills. These three pillars form the backbone of BUMMP, empowering students from all backgrounds and ensuring their retention and persistence in STEM. So far, we've served over 1350 mentees, collaborated with 809 mentors, and had over 180 mentees actively engaged in BUMMP‐sponsored research activities. The primary focus of this paper is to provide a programmatic guideline for the three pillars of BUMMP: mentorship, professional development, and research. This will offer a blueprint for other institutions to establish similar mentorship programs. Additionally, the paper highlights the impact of the BUMMP program and surveyed mentees who have participated in the mentorship and research component of BUMMP. We showed that mentorship and research experience enhance students' sense of belonging, science identity, and science efficacy, which are key predictors of retention and persistence in pursuing a STEM career. Overall, BUMMP's expansive efforts have made a tremendous impact at UC San Diego and will continue to foster a community of future leaders who will be prepared to make meaningful contributions to the scientific community and beyond. 

Abstract Nearly one‐third of nascent proteins are initially targeted to the endoplasmic reticulum (ER), where they are correctly folded and assembled before being delivered to their final cellular destinations. To prevent the accumulation of misfolded membrane proteins, ER‐associated degradation (ERAD) removes these client proteins from the ER membrane to the cytosol in a process known as retrotranslocation. Our previous work demonstrated that rhomboid pseudoprotease Dfm1 is involved in the retrotranslocation of ubiquitinated membrane integral ERAD substrates. Herein, we found that Dfm1 associates with the SPOTS complex, which is composed of serine palmitoyltransferase (SPT) enzymes and accessory components that are critical for catalyzing the first rate‐limiting step of the sphingolipid biosynthesis pathway. Furthermore, Dfm1 employs an ERAD‐independent role for facilitating the ER export and endosome‐ and Golgi‐associated degradation (EGAD) of Orm2, which is a major antagonist of SPT activity. Given that the accumulation of human Orm2 homologs, ORMDLs, is associated with various pathologies, our study serves as a molecular foothold for understanding how dysregulation of sphingolipid metabolism leads to various diseases. 

Rhomboid proteases are ubiquitous intramembrane serine proteases that can cleave transmembrane substrates within lipid bilayers. They exhibit many and diverse functions, such as but not limited to, growth factor signaling, immune and inflammatory response, protein quality control, and parasitic invasion. Human rhomboid protease RHBDL4 has been demonstrated to play a critical role in removing misfolded proteins from the endoplasmic reticulum and is implicated in severe diseases such as various cancers and Alzheimer's disease. Therefore, RHBDL4 is expected to constitute an important therapeutic target for such devastating diseases. Despite its critical role in many biological processes, the enzymatic properties of RHBDL4 remain largely unknown. To enable a comprehensive characterization of RHBDL4's kinetics, catalytic parameters, substrate specificity, and binding modality, we expressed and purified recombinant RHBDL4 and employed it in a Förster resonance energy transfer-based cleavage assay. Until now, kinetic studies have been limited mostly to bacterial rhomboid proteases. Our in vitro platform offers a new method for studying RHBDL4's enzymatic function and substrate preferences. Furthermore, we developed and tested potential inhibitors using our assay and successfully identified peptidyl α-ketoamide inhibitors of RHBDL4 that are highly effective against recombinant RHBDL4. We utilize ensemble docking and molecular dynamics simulations to explore the binding modality of substrate-derived peptides bound to RHBDL4. Our analysis focused on key interactions and dynamic movements within RHBDL4's active site that contributed to binding stability, offering valuable insights for optimizing the nonprime side of RHBDL4 ketoamide inhibitors. In summary, our study offers fundamental insights into RHBDL4's catalytic activities and substrate preferences, laying the foundation for downstream applications such as drug inhibitor screenings and structure-function studies, which will enable the identification of lead drug compounds for RHBDL4. 

Protein aggregates are a common feature of diseased and aged cells. Membrane proteins comprise a quarter of the proteome, and yet, it is not well understood how aggregation of membrane proteins is regulated and what effects these aggregates can have on cellular health. We have determined in yeast that the derlin Dfm1 has a chaperone-like activity that influences misfolded membrane protein aggregation. We establish that this function of Dfm1 does not require recruitment of the ATPase Cdc48 and it is distinct from Dfm1’s previously identified function in dislocating misfolded membrane proteins from the endoplasmic reticulum (ER) to the cytosol for degradation. Additionally, we assess the cellular impacts of misfolded membrane proteins in the absence of Dfm1 and determine that misfolded membrane proteins are toxic to cells in the absence of Dfm1 and cause disruptions to proteasomal and ubiquitin homeostasis.