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Alfred “Fred” Goldberg, Ph.D., (born 1942) is an American cell biologist and professor at Harvard University. He is widely regarded for his work in the pathways for the cellular breakdown of proteins (ubiquitin-proteasome path) and the proteasome's discovery. Bacteria and mitochondria have this ubiquitin-proteasome pathway. It has a role in destroying misfolded proteins and maintaining cellular homeostasis.

Early Life and Education
Alfred Goldberg was born in 1942. He began his educational journey in 1963 when he graduated with his AB Biochemical degree from Harvard University. After studying some physiology as a Churchill Scholar at Cambridge University and attending Harvard’s Medical School for two years, he went back to Harvard University. Goldberg graduated in 1968 with a Ph.D. in Physiology. Goldberg married his wife, Joan, seven months after meeting in Harvard Medical School’s cafeteria, and they both have a passion for teaching and knowledge.

Career
Goldberg has been a member of the Harvard faculty since graduating in 1968, occupying positions as a professor in physiology, cell and molecular physiology, and finally, cell biology. He co-founded the company that created Bortezomib, a proteasome inhibitor and anti-cancer medication for multiple myeloma. He currently heads the Goldberg Lab in the Department of Cell Biology at Harvard Medical School.

Current Research
His current research is focusing on breaking down cellular proteins. Misfolded proteins occur due to mutations or various damage at stages of formation. Proteasomes breakdown the misfolded proteins when they are misfolded to maintain cellular homeostasis and as a defense mechanism. When proteins are allowed to continue misfolded, other issues, such as cancer, may arise. The Goldberg Lab at Harvard Medical School is studying the various mechanisms that control protein breakdown regulation in cells. They are focusing on both bacterial and animal cells with a concentration of animal skeletal muscle and reticulocytes.

Goldberg is focusing on the ATP-dependent pathway that hydrolyzes the proteins. He works to understand the enzymes' mechanisms and selectivity that hydrolyze proteins and apply them to recognizing and abolishing misfolded or other detrimental proteins. They are renowned for discovering the ubiquitin-dependent pathway and function of proteasomes in immunology in antigen presentation.

On top of the ATP-dependent pathway, the Goldberg lab looks towards how hormones, diet, activity, and diseases in skeletal muscle cells affect protein breakdown. This knowledge will be used for muscle atrophy and growth control and a better understanding of overall body homeostasis.

2020: ClpX Is Essential and Activated by Single-Strand DNA Binding Protein in Mycobacteria
This experiment aimed to understand and define the contributions of ClpP1P2, a proteolytic complex, in growing mycobacteria. The hope was in understanding the function and mechanisms of ClpP1P2 and how essential ClpP1P2 is for bacterial growth. They discovered something they were not anticipating: ClpP1P2 plays a role in DNA replication and maintenance concerning SSB, or single-stranded binding proteins, that keep the single-stranded DNA apart so replication can occur. Replication would halt without ClpP1P2. On an aside, ClpP1P2 is also a good contender for drugs targeting tuberculosis {{Cite journal|last=Kester|first=Jemila C.|last2=Kandror|first2=Olga|last3=Akopian|first3=Tatos|last4=Chase|first4=Michael R.|last5=Zhu|first5=Junhao|last6=Rubin|first6=Eric J.|last7=Goldberg|first7=Alfred L.|last8=Fortune|first8=Sarah M.|date=2021-01-25|title=ClpX Is Essential and Activated by Single-Strand DNA Binding Protein in Mycobacteria|url=https://pubmed.ncbi.nlm.nih.gov/33229461/|journal=Journal of Bacteriology|volume=203|issue=4|doi=10.1128/JB.00608-20|issn=1098-5530|pmc=7847540|pmid

2020: Multiple myeloma cells are exceptionally sensitive to heat shock, which overwhelms their proteostasis network and induces apoptosis
Bortezomib (BTZ) is a proteasome inhibitor for the treatment of multiple myeloma. There are a few reasons that myeloma cells are susceptible to proteasome inhibition, and the main reason is that abnormal immunoglobulins are continuously being produced and destroyed in these cells. This experiment tested the hypothesis that heat shocking myeloma cells may also be as toxic as proteasome inhibition due to its effect on protein folding. If the protein cannot fold correctly, it cannot function correctly. Heat shocking the cells would prevent homeostasis, meaning that the cancerous myeloma cells could not survive the treatment. After shifting four myeloma lines and nine non-myeloma lines from 37 degrees Celsius to 43 degrees Celsius, an MTS assay measured their viability. The four myeloma lines had dramatically reduced viability after 20 hours in the heat shock environment, while the non-myeloma lines did not (or showed little loss). The lab monitored whether heat shocking the myeloma cells affected their susceptibility to proteasome inhibitors, which it did. Heat shocking the cells made them more susceptible to proteasome inhibition, and, therefore, they both disrupt and kill the cells in similar ways: disruptions in protein folding {{Cite web|title=Alfred L. Goldberg, PhD - DF/HCC|url=https://www.dfhcc.harvard.edu/insider/member-detail/member/alfred-l-goldberg-phd/|access-date=2021-04-14|website=www.dfhcc.

2020: Multiple myeloma cells are exceptionally sensitive to heat shock, which overwhelms their proteostasis network and induces apoptosis
Bortezomib (BTZ) is a proteasome inhibitor for the treatment of multiple myeloma. There are a few reasons that myeloma cells are susceptible to proteasome inhibition, and the main reason is that abnormal immunoglobulins are continuously being produced and destroyed in these cells. This experiment tested the hypothesis that heat shocking myeloma cells may also be as toxic as proteasome inhibition due to its effect on protein folding. If the protein cannot fold correctly, it cannot function correctly. Heat shocking the cells would prevent homeostasis, meaning that the cancerous myeloma cells could not survive the treatment. After shifting four myeloma lines and nine non-myeloma lines from 37 degrees Celsius to 43 degrees Celsius, an MTS assay measured their viability. The four myeloma lines had dramatically reduced viability after 20 hours in the heat shock environment, while the non-myeloma lines did not (or showed little loss). The lab monitored whether heat shocking the myeloma cells affected their susceptibility to proteasome inhibitors, which it did. Heat shocking the cells made them more susceptible to proteasome inhibition, and, therefore, they both disrupt and kill the cells in similar ways: disruptions in protein folding.

2020: cGMP via PKG activates 26S proteasomes and enhances degradation of proteins, including ones that cause neurodegenerative diseases
cAMP, cyclic adenosine monophosphate, is a derivative of ATP and essential for many biological functions. It enhances 26S proteasome activity for degradation. This experiment tested whether cGMP can work the same way and as efficiently, if not more efficiently, than cAMP. The scientists added phosphodiesterase 5 to different cell lines to augment misfolded proteins' breakdown and activate protein kinase G (PKG) for 26S proteasome stimulation. cGMP does not affect lysosomal proteolysis, unlike cAMP, and will be more useful in the long run. The lab treated tauopathy zebrafish and zebrafish plagued with Huntington’s disease with a PDE5 inhibitor, causing abnormalities before adding PKG, in conjunction with increased cGMP, to degrade the misfolded and nonfunctional proteins. The addition of raising cGMP and its corresponding stimulators and inhibitors of PDE5 increased proteasome activity.

2020: Proteins containing ubiquitin-like (Ubl) domains not only bind to 26S proteasomes but also induce their activation
26S proteasomes must activate during degradation by binding to ubiquitylated substrates and then deubiquitylase Usp14/Ubp6. This experiment tested seven proteins containing UbI for their role in 26s proteasome activation. Rpn1 allowed Rad23A and Rad23B to simulate the proteasome in question and amplify its function via increasing peptide hydrolysis.

2019: SIP/CacyBP promotes autophagy by regulating levels of BRUCE/Apollon, which stimulates LC3-I degradation
Apoptosis, signaled cell death, perpetuates ubiquitin ligase sending another signal to degrade BRUCE, a membrane-associated inhibitor of apoptosis. This experiment was to show that coupling BRUCE and a proteasome activator will inhibit autophagy. Typically, SIP, a ubiquitination-related protein, degrades BRUCE and, coupled with Rab8, enhances that degradation. The experiment supported that BRUCE and SIP regulate both cell death and autophagy.

2019: 26S Proteasomes are rapidly activated by diverse hormones and physiological states that raise cAMP and cause Rpn6 phosphorylation
This experiment tested whether proteasome activation can occur similarly to 26S activation under hormone and physiological conditions. They treated mouse hepatocytes to stimulate protease activity and then discovered that in vivo proteasome activity through cAMP and PKA stimulation is similar to cellular responses to different environmental reactions.

Accolades and Accomplishments
Goldberg is also a member of the Institutes of Medicine of the National Academy of Science and a fellow of the American Academy of Arts and Sciences. He is among the 1% most cited scientists in the life science, and his awards include:


 * Novartis-Drew Award for Biochemical Science
 * Severo Ochoa Award (New York University)
 * Knobil Prize for Medical Research (University of Texas Medical School)
 * Gabbay Award for Biotechnology and Medicine (Brandeis University)
 * Honorary degrees from both Cold Spring Harbor Laboratories and the University of Maastricht (Netherlands)

He has also lectured at the following prestigious forums:
 * Nobel Forum Lecture (Karolinska Institute)
 * Fay Lecture (University of Massachusetts Medical School)
 * da Vinci Lecture (University of Milan)
 * Rothchild Lecture (Israeli Academy of Sciences)
 * Centennial Lecture (Biochemical Society)

Publications
Alfred Goldberg has authored more than 400 publications. Below are the publications from the Goldberg Lab Department of Cell Biology at Harvard Medical School:

Zhao, J., Garcia, GA., Goldberg, AL. Control of proteasomal proteolysis by mTOR. Nature 2016 Jan 21;529(7586):E1-2. doi 10.1038/nature16472.

Myeku, N, Kukushkin, N, Clelland, CL, Shaler, TA, Figueroa, Y, Herman, M, Kaiser, SE, Yu, WH, Goldberg, AL, and Duff, KA. Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. Nature, 2016 Jan;22(1): 46-53. Doi:10.1038/nm.4011

Li, M, Kandror, O, Akopian, T, Dharkar, P, Woldawer, A, Maurizi MR, Goldberg, AL. Structure and functional properties of the active form of the proteolytic complex, ClpP1P2 from Mycobacterium tuberculosis. J Biol Chem, 2016 Apr 1;291(14):7465-76. Doi: 10.1074/jbc.M115.700344.

Famulla K, Sass P, Malik I, Akopian T, Kandror O, Alber M, Hinzen B, Ruebsamen-Schaeff H, Kalscheuer R, Goldberg AL, Brotz-Oesterhelt H. Acyldepsipeptide antibiotics kill mycobacteria by preventing the physiological functions of the ClpP1P2 protease. Mol Microbiol. 2016 Jul;101(2):194-209. Doi: 10.1111/mmi.13362

Lee, DH., Sherman, MY., Goldberg, AL. The requirements of yeast Hsp70 of SSA family for the ubiquitin-dependent degradation of short-lived and abnormal proteins. Biochem Biophys Res Commun. 2016 Jun 17;475(1):100-6. Doi: 10.1016/j.bbrc.2016.0046.

Zhao, J and Goldberg, AL. Coordinate regulation of autophagy and the ubiquitin proteasome system by mTOR. Autophagy. 2016 Oct 2;12(10):1967-1970. Doi: 10.1080/15548627.2011205770.

Alexopoulou Z, Lang J, Perrett RM, Elschami M, Hurry ME, Kim HT, Mazaraki D, Szabo A, Kessler BM, Goldberg AL, Ansorge O, Fulga TA, Tofaris GK. Deubiquitinase Usp8 regulates α-synuclein clearance and modifies its toxicity in Lewy body disease. Proc Natl Acad Sci USA. 2016 Aug 9;113(32):E4688-9 Doi: 10.1073/pnas. 1523597113.

Alfred L. Goldberg: Probing the Proteasome. Trends Cell Biol. 2016 Sep 24. Pii: S0962-8924(16)30133-7. Doi: 10.1016/j.tcb.2016.09.003.

Sha Z and Goldberg AL. Reply to Vangala et al.: Complete inhibition of the proteasome reduces new proteasome production by causing Nrf1 aggregation. Curr Biol. 2016 Sep 26;26(18):R836-7. Doi: 10.1016/j.cub.2016.08.030.

Weyburne ES, Wilkins OM, Sha Z, Goldberg AL, Cole MD, Kisselev AF. Inhibition of the proteasome β2 site sensitizes triple-negative breast cancer cells to β5 inhibitors and suppresses Nrf1 activation. Cell Chem Biol. 2017; 24(2):218-230. Doi: 1016/j.chembiol.2016.12.016.

Volodin A, Kosti I, Goldberg AL, Cohen S. Myofibril breakdown during atrophy is a delayed response requiring the transcription factor PAX4 and desmin depolymerization. Proc Natl Acad Sci U S A. 2017; 114(8):E1375-E1384. Doi: 10.1073/pnas.1612988114.

VerPlank JJS, Lokireddy S, Feltri ML, Goldberg AL, Wrabetz L. Impairment of protein degradation and proteasome function in hereditary neuropathies. Glia. 2018 Feb;66(2): 379-395. Doi: 10.1002/glia.23251. Epub 2017 Oct 27. PubMed PMID: 29076578

Kim, HT and Goldberg, AL. The deubiquitinating enzyme Usp14 allosterically inhibits multiple proteasomal activities and ubiquitin-independent proteolysis. J Biol Chem. 2017 Apr 17. Pii:jbc.M116.763128. Doi: 10.1074/jbc.M116.763128.

Kuo, C-L and Goldberg, AL. Ubiquitinated proteins promote the association of proteasomes with the deubiquitinating enzyme Usp14 and the ubiquitin ligase Ube3c. Proc Natl Acad Sci U S A. 2017 Apr 25; 114(17):E3404-E3413. Doi: 10.1073/pnas.17017341

Collins, GA and Goldberg, AL. The Logic of the Proteasome. Cell. 2017 May 18;169(5):792-806. Doi: 10.1016/j.cell.2017.04.023.

VerPlank, J and Goldberg, AL. Regulating Protein Breakdown Through Proteasome Phosphorylation. Biochemical Journal. 2017. 474:3355-3371. Doi: 10.1042/BCJ20160809.

Sha Z, Schnell HM, Ruoff K, and Goldberg AL. Rapid induction of p62 and GABARAPL1 upon proteasome inhibition promotes survival before autophagy activation. J Cell Biol. 2018; 217(5). Doi: 10.1083/jcb.201708168. PubMed PMID: 29535191

Weinhaupl K, Brennich M, Kazmaier U, Lelievre J, Ballell L, Goldberg AL, Schanda P, Fraga H. The antibiotic cyclomarin blocks arginine-phosphate-induced millisecond dynamics in the N-terminal domain of ClpC1 from Mycobacterium tuberculosis. J Biol Chem. 2018 Jun 1; 293 (22): 8379-8393. Doi: 10.1074/jbc.RA118.002251.

Lee D, Takayama S, Goldberg AL. ZFAND5/ZNF216 is a novel activator of the 26S proteasome that stimulates overall protein degradation. Proc Natl Acad Sci U S A. 2018; 115(41):E9550-E9559. Doi: 10.1073/pnas.1809934115.

Kim HT and Goldberg AL. The UBL domain of Usp14 and other proteins stimulates proteasome activities and overall protein degradation in cells. Proc Natl Acad Sci U S A. 2018;115(50):E11650. Doi: 10.1073/pnas.1808731115.

Fraga H, Rodriguez, Bardera A, Cid C, Akopian T, Kandror O, Park A, Colmenarejo G, LeLievre J, Goldberg AL. Development of high throughput screening methods for inhibitors of ClpC1P1P2 from Mycobacteria tuberculosis. Analytical Biochemistry. 2019. 567: 30-37. Doi: 10.1016/j.ab.2018.12.004.

VerPlank J, Lokireddy S, Zhao J, Goldberg AL. 26S Proteasomes are rapidly activated by diverse hormones and physiological states that raise cAMP and cause Rpn6 phosphorylation. Proc Natl Acad Sci U S A. 2019. Doi: 10.1073/pnas.1809254116.