Biology subjects

Lo, I.-C.

Publications and source records attributed to Lo, I.-C..

3 recordsLinked to original sources

bioRxiv2024

Suppression of NRF2-dependent cancer growth by a covalent allosteric molecular glue

The NRF2 transcription factor is constitutively active in cancer where it functions to maintain oxidative homeostasis and reprogram cellular metabolism. NRF2-active tumors exhibit NRF2-dependency and resistance to chemo/radiotherapy. Here we characterize VVD-065, a first-in-class NRF2 inhibitor that acts via an unprecedented allosteric molecular glue mechanism. In the absence of stress or mutation, NRF2 is rapidly degraded by the KEAP1-CUL3 ubiquitin-ligase complex. VVD-065 specifically and covalently engages C151 on KEAP1, which in turn promotes KEAP1-CUL3 complex formation, leading to enhancement of NRF2 degradation. Previously reported C151-directed compounds decrease KEAP1-CUL3 interactions and stabilize NRF2, thus establishing KEAP1_C151 as a tunable regulator of the KEAP1-CUL3 complex and NRF2 stability. VVD-065 inhibited NRF2-dependent tumor growth and sensitized cancers to chemo/radiotherapy, supporting an open Phase I clinical trial (NCT05954312).

cancer biology↗

bioRxiv2021

Closed-Loop Control between Two GTPase Switches makes the Secretory Functions of the Golgi Responsive to Growth Factors

Cancers represent complex autonomous systems, displaying self-sufficiency in growth signaling. Autonomous growth is fueled by a cancer cells ability to secrete-and-sense growth factors: a poorly understood phenomenon. Using an integrated systems and experimental approach, here we dissect the impact of a feedback-coupled GTPase circuit within the secretory pathway that imparts secretion-coupled autonomy. The circuit is assembled when the Ras-superfamily monomeric GTPase Arf1, and the heterotrimeric GTPase Gi{beta}{gamma} and their corresponding GAPs and GEFs are coupled by GIV/Girdin, a protein that is known to fuel aggressive traits in diverse cancers. One forward and two key negative feedback loops within the circuit create closed-loop control (CLC), allow the two GTPases to coregulate each other, and convert the expected switch-like behavior of Arf1-dependent secretion into an unexpected dose response alignment behavior of sensing and secretion. Such behavior translates into cell survival that is self-sustained by stimulus-proportionate secretion. Proteomic studies and protein-protein interaction network analyses pinpoint growth factors (e.g., the epidermal growth factor; EGF) as a key stimuli for such self-sustenance. Findings highlight how enhanced coupling of two biological switches in cancer cells is critical for multiscale feedback control to achieve secretion-coupled autonomy of growth factors. SYNOPSIS IMAGE O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY STANDFIRST TEXTThis work defines the inner workings of a Golgi-localized molecular circuitry comprised of coupled GTPases, which empowers cells to achieve self-sufficiency in growth factor signaling by creating a secrete-and-sense autocrine loop. HIGHLIGHTS/MAIN FINDINGSO_LIModeling and experimental approaches were used to dissect a coupled GTPase circuit. C_LIO_LICoupling enables closed loop feedback and mutual control of GTPases. C_LIO_LICoupling generates dose response alignment behavior of sensing and secretion of growth factors. C_LIO_LICoupling is critical for multiscale feedback control to achieve secretion-coupled autonomy. C_LI

systems biology↗

bioRxiv2019

GIV/Girdin and Exo70 Constitute the Core of the Mammalian Polarized Exocytic Machinery

Polarized exocytosis is a fundamental process by which membrane and cargo proteins are delivered to the plasma membrane with precise spatial control; it is essential for cell growth, morphogenesis, and migration. Although the need for the octameric exocyst complex is conserved from yeast to humans, what imparts spatial control is known only in yeast, i.e., a polarity scaffold without mammalian homolog, called Bem1p. We demonstrate that polarity scaffold GIV/Girdin fulfills the key criteria and functions of its yeast counterpart Bem1p. Both Bem1p and GIV bind yeast and mammalian Exo70 proteins via similar short-linear interaction motifs, but each preferentially binds its evolutionary counterpart. In cells where this GIV*Exo-70 interaction is selectively disrupted, delivery of the metalloprotease MT1-MMP to podosomes, collagen degradation and haptotaxis through basement membrane matrix were impaired. GIVs interacting partners reveal other components of polarized exocytosis in mammals. Findings not only expose how GIV "upgrades" the exocytic process in mammals, but also how the ability to regulate exocytosis shapes GIVs ability to fuel metastasis. GRAPHIC ABSTRACT O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY Graphic Abstract: Schematic comparing the components of polarized exocytosis, i.e., the major polarity scaffold in yeast (Bem1p; left) and humans (Girdin; right) and the various cellular components and signaling mechanisms that are known to converge on them. C_FIG_DISPLAY The eTOC blurbPolarized exocytosis is a precision-controlled process that is enhanced in disease states, e.g., cancer invasion; what imparts polarity was unknown. Authors reveal how the process underwent an evolutionary upgrade from yeast to humans by pinpointing GIV/Girdin as the polarity scaffold which orchestrates the exocytosis of matrix metalloproteases during cell invasion. HIGHLIGHTSO_LIGIV (human) and Bem1p (yeast) bind Exo70; are required for exocytosis C_LIO_LIGIV binds and aids PM localization Exo70 via a conserved short linear motif C_LIO_LIBinding facilitates MT1-MMP delivery to podosomes, ECM degradation, invasion C_LIO_LIRegulatory control over polarized exocytosis is upgraded during evolution C_LI

cell biology↗