Immunology Faculty Member - Paul Anderson, MD, PhD

Paul Anderson, MD, PhD

Department of Medicine; Division of Rheumatology
Brigham and Women's Hospital, Smith 652
One Jimmy Fund Way
Boston, MA 02115

Tel: 617-525-1202
Fax: 617-525-1310
Email: panderson@rics.bwh.harvard.edu
Lab Members: 6 Postdoctoral Fellows, 1 Graduate PhD Student



My current research activities are in the following areas: 1) Composition and function of mammalian stress granules, 2) Angiogenin-induced tRNA cleavage, and 3) Post-transcriptional regulation of inflammatory cytokine production. Work in my laboratory is focused on the post-transcriptional mechanisms that regulate environmental stress and inflammation. In 1990, my laboratory discovered stress granules (SGs), ribonucleoprotein complexes that include translationally stalled mRNAs in cells exposed to adverse environmental conditions. Over the last 15 years, work in the lab has established the composition of SGs, signaling pathways that lead to SG assembly, and roles for SGs in promoting cell survival. In 2007, we discovered that environmental stress activates angiogenin, a ribonuclease that cleaves tRNA in anticodon loops to produce 5’- and 3’-tiRNAs, small non-coding RNAs that target the translational machinery to re-program gene expression and induce SG assembly. Because point mutants that inactive the ribonuclease activity of angiogenin have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), these studies suggests that selected tRNA fragments have cytoprotective effects required for motoneuron survival. We have identified tiRNA analogs that are lead compounds for the development of a new class of drug for the treatment of ALS.

Work in the lab has also identified post-transcriptional control mechanisms that dampen the translation of mRNAs encoding inflammatory mediators. Many mRNAs that encode inflammatory mediators (e.g. TNF-
a, IL-1β, COX-2, matrix metalloproteinase) possess adenine and uridine-rich elements (AREs) in their 3’ untranslated regions that inhibit translation and promote mRNA decay. The regulated activity of ARE-binding proteins (ARE-BPs) is required to overcome constitutive translational repression and mRNA instability. TIA-1, TIAR and TTP are ARE-BPs that prevent the pathological overexpression of inflammatory mediators. TIA-1 and TIAR inhibit the translation of TNF-a, COX-2 and MMP-13 transcripts, whereas TTP promotes the degradation of TNF-α and COX-2 transcripts. Because of this, TIA-1 and TTP function as arthritis suppressor genes: TIA-1-/- mice develop mild arthritis, TTP-/- mice develop severe arthritis and TIA-1/TTP-/- female mice develop very severe arthritis. Whereas macrophages are a major source of arthritigenic cytokine in mice lacking TIA-1 or TTP, neutrophils are a major source of arthritigenic cytokine in mice lacking both TIA-1 and TTP. Thus, TIA-1 and TTP are genetic modifiers of inflammatory arthritis that can alter the spectrum of cells that produce arthritigenic cytokine.

TIA-1 and TTP also regulate the general translational arrest observed in cells subjected to environmental stress. Both TIA-1 and TTP regulate the assembly of cytoplasmic stress granules, discrete foci at which untranslated mRNAs accumulate in stressed cells. Stress-induced phosphorylation of the translation initiation factor eIF2
a allows TIA-1 to promote the assembly of untranslated, non-canonical 48S preinitiation complexes that are the core constituents of stress granules. We have proposed that stress granules function as sites of mRNA triage: by monitoring the composition and function of mRNP complexes, the stress granule determines whether individual mRNAs are stored, degraded, or re-initiated.



Last Update: 1/22/2016



Publications

Kedersha N, Ivanov P, Anderson P. Stress granules and cell signaling: more than just a passing phase? Trends Biochem Sci. 2013; Oct;38(10):494-506. PMC3832949

Anderson P, Ivanov P. tRNA fragments in human health and disease. FEBS Lett. 2014 Nov 28; 588(23):4297-4304.

Anderson P, Kedersha N, Ivanov P. Stress granules, P-bodies and cancer. Biochim Biophys Acta. 2014 Dec 5. PMC4457708 [Available on 2016-07-01]

Ivanov P, O’Day E, Emara MM, Wagner G, Lieberman J, Anderson P. G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments. Proc Natl Acad Sci U S A. 2014 Dec 23; 111(51):18201-6.



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