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WEAVER LAB

UT SOUTHWESTERN MEDICAL CENTER

DEPARTMENT of PHARMACOLOGY

 

PROTEOLYTIC MECHANISMS in CELL SIGNALING

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We work at the cross-roads of development, aging and stress responses.  A major focus of our studies is to understand the nature of gene-environment interactions. We want to reveal how these interactions were sculpted through evolution and how they impact normal as well as pathological processes.

How do cells transition between different states?  What factors are required to switch into and out of stress responses or shift from a precursor state to a descendant cell fate in development?  How do developmental and stress response pathways impact each other?  Despite considerable effort and impact to many disease states from cancer to neurodegeneration, there remains little understanding of the mechanisms governing these important cellular decisions.  If we understood the underlying rules of these processes, could we alter the trajectory of outcomes?  We are setting out to unmask the proteolytic regulators of these signaling pathways.

Proteolytic factors regulate signaling by imposing irreversible commitment to protein modification.  Current lines of inquiry include: (1) understanding cell state transitions in development and stress responses, (2) unmasking proteolytic-mediated metabolic signaling in stress responses and (3) revealing the impact of proteostasis in aging. Our long-term objective is to illuminate the conserved programs regulating these fundamental cellular processes.

Deciphering these novel regulatory paradigms is essential to understanding a broad spectrum of disease processes. Pathological outcomes reflect critical tradeoffs of cell turnover, cell fate, or tuning of stress responsiveness such as in the contexts of cancers, degenerative diseases, and immune disorders. These maladies underscore the importance of cells to sense their internal and external environments and respond accordingly. How cells and tissues integrate diverse inputs during development and aging remain wide open areas of research. Our goal is to resolve these long-standing mysteries. ​

HIGHLIGHTS

May 2024
Looking ahead...
Fingers crossed!! More papers coming soon!

Just half way into 2024 and we have 2 more additional manuscripts in review at the same time!!

Stay tuned!!

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We got the cover of Nature Metabolism!!

January 2024 Issue

See story below on decoding resolution after stress

What an amazing way to kick off the new year!

Special thanks to our collaborators: Ralph, Matt, Courtney and Yuan--thank you all!!

Nature  Metabolism
January 2024
Decoding Resolution after Stress

Combining metabolomics, transcriptomics, genetic screens and cell biology approaches, we revealed CED-3 caspase proteolytically activates the C-terminal fragment of fatty acid synthase (FASN-CTF) to signal stress resolution. This unexpected FASN signaling function is independent of fatty acid synthesis. Activation of the FASN-CTF fragment shuts down innate immunity and UPR gene expression, resolves lipid droplets and switches metabolic programs.

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Nature Communications
July 2023
Maintaining Neurons during Aging

Excellent collaboration with Melanie!

Combining biochemistry with cell biology and mass-spec analyses, we revealed a non-apoptotic caspase function targets p38 MAPK to control signaling output supporting lysosome homeostasis and neuronal integrity during aging when germline is left intact. This paper also revealed that phosphoratio not just absolute of phospho levels modulate net signaling.

Developmental Cell
May 2020
Antagonizing Stress with Development

Combining ribosome profiling with genetic and biochemical analyses, we revealed CED-3 caspase limits pathogen stress response during development by blocking p38 MAPK innate immunity gene expression. This circuit balances development rate with stress responsiveness.

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PEOPLE

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DR. BENJAMIN WEAVER


Principal Investigator

  

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DR. YI MIAO WEAVER


Sr. Research Scientist

 

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DR. WANG YUAN

Post-Doctoral Researcher


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DR. HAI WEI

Post-Doctoral Researcher

 

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DR. FRANCISCO CALVA MORENO

MSTP Program

Defended Ph.D.

May 2024

Center for Regenerative Science and Medicine Fellowship

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Lab Alumnus
TATIANA
FERREIRA

2023

Fall Rotation Student

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Lab Alumnus
PRERITH ARUNKMAR

2023

STARS Summer Student

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Lab Alumnus
GEORGE JOSE

 

2023

Green Fellow

Spring Semester

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Lab Alumnus
IRVIN GARZA

2022

Fall Rotation Student

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Lab Alumnus
RYAN OTTO

2019

Summer Rotation Student

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WE ARE STILL
RECRUITING!

 

Excellent time to join the lab!!

Graduate student applicants: Apply through the umbrella

Ph.D. Program and send Ben an email of interest.

Post-Doc and Technician Applicants: send Ben your letter of interest.

RESEARCH

Current Priorities and Training Environment

The Weaver lab is multidisciplinary and employs state of the art methods combining genetics, proteomics, transcriptomics, metabolomics, advanced imaging and biophysical analyses. We utilize C. elegans, mammalian cell culture, and in vitro models. Equipped with powerful tools, we are setting out to understand how proteolytic mechanisms regulate basic biological processes and how these activities are integrated across tissues within animals. Trainees will learn cutting-edge methodologies in diverse disciplines. We are actively working on several exciting fronts. Now is an exceptional time to join the lab and learn advanced technologies and methods to examine fundamental biological problems.

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CELL SIGNALING

As an emerging regulatory paradigm, our unpublished findings suggest an array of genes work with caspases to support the viability of cells. Using proteomic, genetic, and cell biology approaches, we are probing how proteolytic factors integrate diverse inputs to mediate cellular outputs. Several grand challenges to solve include: (1) Will these pathways act discretely to regulate independent sets of genes or act broadly coordinating many processes? (2) What developmental and environmental signals activate or inhibit these proteolytic functions? (3) How are these proteolytic functions compartmentalized within a cell to prevent activating cell death? and (4) How does alteration of these pathways contribute to diverse disease processes? Solving these fundamental cellular processes will be broadly illuminating.

STRESS & AGING

Throughout metazoans, p38 MAPKs are critical to initiate stress responses. We recently showed that CED-3 caspase antagonizes a p38 MAPK-dependent pathogen response to promote development.
We are using advanced CRISPR methods combined with omics-based approaches and advanced imaging to understand how this pathway is dynamically regulated throughout animal lifespan. What tissues are important for p38 MAPK regulation within an animal? Beyond innate immunity, does p38 MAPK regulate other targets?

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CELL FATE

We previously demonstrated that a non-canonical caspase function is necessary for temporal cell fate patterning to limit symmetric cell divisions at a critical developmental window. We are expanding these studies to understand the roles of other proteolytic factors in cell fate decisions.

DIFFERENTIAL REGULATION

Across nematodes, flies, and mammals, caspases have been found with critical non-canonical functions blocking stemness and supporting differentiation.  We are using genetic and biochemical methods to understand how a given caspase with both cell death and stemness-blocking functions is distinctly regulated.

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SUBSTRATE RECOGNITION

We recently showed that CED-3 caspase requires a UBR-type E3 ubiquitin ligase to efficiently cleave and degrade LIN-28 in vivo. We further showed that the caspase and E3 ligase physically interact. We are using biochemical and biophysical methods to understand how proteolytic factors recognize distinct substrates.

SELECTED PUBLICATIONS

2024

Proteolytic Activation of Fatty Acid Synthase Signals Pan-Stress Resolution

Wei H, Weaver YM, Yang C, Zhang Y, Hu G, Karner CM, Sieber M, DeBerardinis RJ, Weaver BP

Nature Metabolism 6, 113-126 (2024)

Featured in News & Views: Cutting through the Stress

Luis Jasper and Meng Wang Nature Metabolism 2024

Also featured on the cover!! "FASN cuts stress"  Nature Metabolism Jan 2024

2023

Modulating p38 MAPK Signaling by Proteostasis Mechanisms Supports Tissue Integrity during Growth and Aging

Yuan W, Weaver YM, Earnest S, Taylor CA, Cobb MH, Weaver BP

Nature Communications 14, 4543 (2023)

​2020

Non-Canonical Caspase Activity Antagonizes p38 MAPK Stress-Priming Function to Support Development

Weaver BP*, Weaver YM, Omi S, Yuan W, Ewbank JE, Han M 

Developmental Cell 53(3):  358-369

*Corresponding Author

Featured in Development or Disease: Caspases Balance Growth and Immunity in C. elegans

Olya Yarychkivska and Shai Shaham Developmental Cell 53(3): 259-260

2018

Tag team: Roles of miRNAs and Proteolytic Regulators in Ensuring Robust Gene Expression Dynamics.

Weaver BP*, Han M

Trends in Genetics. 34(1):21-29   

*Corresponding Author


2017

 

Coupled Caspase and N-End Rule Ligase Activities Allow Recognition and Degradation of Pluripotency Factor LIN-28 during Non-Apoptotic Development.

​Weaver BP*, Weaver YM, Mitani S, Han M

Developmental Cell 41(6):665-673

*Corresponding Author   

Featured in Partners in Crime

Barbara Conradt Developmental Cell 41(6):  573-574

2016

 

Time to move the fat.

Weaver BP*, Sewell AK, Han M

Genes & Development 30(13):1481-1482   

*Corresponding Author

2014
 

CED-3 caspase acts with miRNAs to regulate non-apoptotic gene expression dynamics for robust development in C. elegans.

Weaver BP, Zabinsky R, Weaver YM, Lee ES, Xue D, Han M

eLife e04265

Featured in Development: Cell Death Machinery Makes Life More Robust

Cristina Aguirre-Chen and Christopher M Hammell eLife 3:e05816

Also featured in For Caspases, An Escape from Death

Beverly A Purnell Science 347(6218): 142-143

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LAB NEWS

May 2024

Fingers Crossed!

2 more papers in review at the same time!

May 2024

Congratulations Dr. Calva Moreno!

Francisco successfully defended his PhD!

March 2024

Excellent Visit!

Ben was honored to give a seminar at the OHRI in Ottawa Canada and talk about all of the cool stuff going on in the Weaver Lab!

February 2024

Congratulations Hai!

Hai's paper made the January cover of Nature Metabolism!

January 2024

Congratulations Hai!

Hai's first-author paper now published in Nature Metabolism!

December 2023

Congratulations Hai!

Hai was honored to receive the...

Alfred & Mabel Gilman Memorial Postdoctoral Excellence in Science Award.

October 2023

Welcome Tatiana!

Joining for a rotation, let's hope Tatiana finds C. elegans as fun as the rest of us do!

August 2023

Congratulations Wang!

Wang's paper was featured at Nature Communications in the collection

"From molecules and cells to organisms"

July 2023

Congratulations Wang!

Wang's first-author paper now published at Nature Communications!

June 2023

Welcome Prerith Arunkumar!

Joining us as a rising Senior, Prerith has chosen to embark on his science journey with us as a STARS student this summer.

May 2023

Excellent Meeting!

Ben gave a talk on the lab's exciting recent findings of FASN in stress responses at the Mechanisms of Metabolic Signaling meeting at Cold Spring Harbor.

May 2023

Congratulations Ben!

Ben is honored to join the 2023 TAMEST meeting as the protege of Dr. David Mangelsdorf Professor and Chair of Pharmacology.

February 2023

Congratulations Yi! 

Yi was honored to receive the Gilman Special Opportunities in Pharmacology Award.

January 2023

Welcome George Jose! 

Joining us as an undergraduate from UT Dallas, George has received a presitigious Green Fellowship and has chosen to spend the spring semester with us for undergraduate research.

November 2022

Congratulations Ben!

Ben was thrilled to deliver the Alvin Sarachek Research Seminar at his alma mater in the Department of Biological Sciences of Wichita State University.

September 2022

Excellent Meeting!

Ben gave a talk about the lab's exciting recent findings on caspase regulation of p38 MAPK signaling controlling neuroprotection during aging at the 2nd international Non-Lethal Roles of Cell Death Proteins meeting in Galway Ireland.

September 2022

Congratualtions Francisco!

Francisco was awarded a prestigious graduate fellowship from the Hamon Center for Regenerative Science and Medicine!

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July 2022

Excellent Meeting!

Ben gave a talk about the lab's exciting recent findings on caspase regulation of p38 MAPK signaling controlling neuroprotection during aging at the Metabolism, Aging, Pathogenesis, and Stress in C. elegans meeting in Madison Wisconsin.

​​July 2022

Congratulations Wang! 

Wang's first author paper posted on bioRxiv

https://doi.org/10.1101/2022.07.12.499791

June 2022

Congratulations Ben!

Ben was honored to join the 2022 TAMEST meeting as the protege of Dr. Melanie Cobb, Professor of Pharmacology.

June 2022

Awesome Jobs Hai and Wang!

Hai gave a terrific talk and Wang gave an exceptional poster at the Physiology retreat!

April 2022

Awesome Job Francisco!

Francisco gave a terrific talk at the CMB graduate symposium!

April 2022

Move is Done!

Everyone pitched in and we finally moved into our newly-renovated space.  Awesome microscopy and tissue culture facilities.

​​May 2021

Congratulations Francisco!

Francisco passed his qualifying exams!

March 2021

Congratulations Wang!

Wang wins the Spring Pretty Gel Competition!

May 2020

Congratulations lab!

Our paper with Yi and Wang is out in Dev Cell!  Good start!

​February 2020

Welcome Dr. Hai Wei! 

After graduate school in Munich, Hai joins the lab for post-doctoral studies.

November 2019

Welcome Francisco Calva Moreno!

Following undergraduate studies in Philly, Francisco joins the lab for graduate studies.

September 2019

Excellent Meeting!

Ben gave a talk about the lab's recent exciting findings on caspase-mediated regulation of pathogen response during development at the 1st international Non-Apoptotic Roles of Cell Death Proteins meeting in Rehovot Israel.

July 2019

Congratulations Weaver Lab!

Ben's MIRA grant funded through NIGMS!

May 2019

Welcome Dr. Wang Yuan! 

After training in Iowa, Wang joins the lab for post-doctoral studies.

April 2019

Congratulations Weaver Lab!

Ben's Welch Foundation grant funded!

September 2018

Weaver Lab established!

Ben and Yi get to work in the Department of Pharmacology at UT Southwestern Medical Center.

Post-Doc Years

Thank You Min and all of the Han Lab!

Ben and Yi worked in Min Han's HHMI lab at CU Boulder where we discovered a non-canonical function for CED-3 caspase and UBR-1 E3 ligase in cell fate determination. 

GALLERY

FUN

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Min hanging out with the Weaver lab on his May 2022 visit to UT Southwestern!!!
Kind of like worlds colliding when your post-doc mentor meets your lab.  Is "science grandpa" a thing?  ;-)

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May 2024 Francisco defends his PhD!!!
Congratulations Dr. Calva Moreno!! 
We all knew you could do it!

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Party food!! 
 

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More party food!!
 

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Physiology Retreat 2022
Dallas Arboretum

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Hai joins the lab, NEW YEARS 2020!!!
Sorry Wang and Francisco...We forgot to take pictures of your celebrations. Oops

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LAB BOWLING PARTY
Celebrating Francisco passing qualifying exam!!

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AGING MEETING 2022

Great colleagues, great science, great weather in Madison...You just can't beat it!

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LAB GOLF PARTY 2023
Celebrating Hai's paper!!
What? That is a smile. Maybe just stunned his paper got accepted and got the cover!!  ;-)

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Cold Spring Harbor May 2023
Mechanisms of Metabolic Signaling meeting was awesome!! Great colleagues and venue!

CONTACT

​Interested in joining?  We would love to hear from you.

 

benjamin.weaver [at] utsouthwestern.edu

Twitter:  @WeaverScience

This website reflects only the views of the author and  is  not  a  publication  of  UT Southwestern,  which  bears  no responsibility for its content.

UT Southwestern Medical Center

Pharmacology

6001 Forest Park Rd

Dallas, TX 75390 USA

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