INT274621

Context Info Confidence 0.80 First Reported 2009 Last Reported 2009 Negated 1 Speculated 0 Reported most in Body Documents 1 Total Number 15 Disease Relevance 1.48 Pain Relevance 0.13

cytosol (PSTPIP1) signal transduction (PSTPIP1) oxidoreductase activity (PSTPIP1) cell adhesion (PSTPIP1) cytoskeleton (PSTPIP1) cytoplasm (PSTPIP1)

Anatomy Link Frequency filaments 5 SH3 2 PSTPIP1 (Homo sapiens)

Pain Link Frequency Relevance Heat Inflammation 135 83.44 Arthritis 30 62.04 Pain 30 5.00

Disease Link Frequency Relevance Heat Syndrome 135 85.20 INFLAMMATION 135 83.44 Disease 150 82.40 Fever 165 73.36 Acne 30 63.32 Pyoderma Gangrenosum 30 62.92 Arthritis 30 62.04 Osteomyelitis 60 5.00 Pain 30 5.00 Adhesions 15 5.00

Sentences Mentioned In

Key:

Protein

Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

In this case, pyrin is localized in 100% of specks, but PSTPIP1 is never localized in specks (Figure 9Q–S).

Localization (localized) of PSTPIP1

1) Confidence 0.80 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2702820 Disease Relevance 0.07 Pain Relevance 0

Taken together, our data support the notion that the increased pyrin binding affinity of PAPA mutations alter the cellular localization of PSTPIP1, bringing it to a compartment in which it might act to intensify inflammasome signaling.

Localization (localization) of PSTPIP1

2) Confidence 0.80 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2702820 Disease Relevance 0.19 Pain Relevance 0.03

Finally, we demonstrate that pyrin can recruit PSTPIP1 into aggregations (specks) of ASC, another pyrin binding protein.

Localization (recruit) of PSTPIP1

3) Confidence 0.75 Published 2009 Journal PLoS ONE Section Abstract Doc Link PMC2702820 Disease Relevance 0.67 Pain Relevance 0.03

This region might also be a PEST phosphatase interaction surface, since pyrin and PEST phosphatase are thought to bind to the same region of PSTPIP1 and the PAPA mutations increase affinity for pyrin while decreasing affinity for PEST phophatases [5].

Localization (phosphatase) of PEST

4) Confidence 0.75 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2702820 Disease Relevance 0 Pain Relevance 0

First, our studies show clearly that the SH3 domain of PSTPIP1 is not required for pyrin binding nor is it necessary for pyrin-mediated reticularization of PSTPIP1 filaments.

Localization (reticularization) of PSTPIP1 in SH3

5) Confidence 0.75 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2702820 Disease Relevance 0 Pain Relevance 0

It was not possible to simultaneously image both pyrin and PSTPIP1 in human cells since both primary antibodies were generated in rabbits.

Localization (image) of PSTPIP1

6) Confidence 0.75 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2702820 Disease Relevance 0 Pain Relevance 0

Additionally, a mutation in the CC region of PSTPIP1, W232A, abolished PSTPIP1 binding both to pyrin [5] and to the PEST phosphatase, PTP-HSCF [8].

Localization (region) of PSTPIP1

7) Confidence 0.75 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2702820 Disease Relevance 0 Pain Relevance 0

We were not able to discern an effect of either pyrin mutations or PSTPIP1 mutations on the property of PSTPIP1 filament reticularization.

Localization (reticularization) of PSTPIP1 in filament

8) Confidence 0.75 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2702820 Disease Relevance 0.17 Pain Relevance 0.03

Additionally, a mutation in the CC region of PSTPIP1, W232A, abolished PSTPIP1 binding both to pyrin [5] and to the PEST phosphatase, PTP-HSCF [8].

Localization (phosphatase) of PEST

9) Confidence 0.75 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2702820 Disease Relevance 0 Pain Relevance 0

We therefore examined the effect of the W232A mutation and the requirement for the SH3 domain on pyrin's recruitment to and reticularization of PSTPIP1 filaments.

Localization (reticularization) of PSTPIP1 in SH3

10) Confidence 0.75 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2702820 Disease Relevance 0 Pain Relevance 0

In contrast, the W232A mutation in PSTPIP1 abolished pyrin binding; consequently, PSTPIP1 filaments were primarily straight, not extensively branched (Figure 4I–K), confirming that the reticularization of PSTPIP1 filaments is a direct consequence of pyrin binding.

Localization (reticularization) of PSTPIP1 in filaments

11) Confidence 0.75 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2702820 Disease Relevance 0 Pain Relevance 0

In addition, we explore the connection between PSTPIP1 filaments and the cellular cytoskeleton and demonstrate that pyrin binding affects PSTPIP1 filament distribution.

Localization (distribution) of PSTPIP1 in filaments

12) Confidence 0.75 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2702820 Disease Relevance 0.17 Pain Relevance 0.04

Pyrin exons 2–4 produced a protein capable of aligning with PSTPIP1 filaments, but the PSTPIP1 filament network was not reticularized (Figure 5E–F).

Neg (not) Localization (reticularized) of PSTPIP1 in filament

13) Confidence 0.75 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2702820 Disease Relevance 0.06 Pain Relevance 0

PSTPIP1 filaments co-localized with DiIC16 staining (Figure 7A–C) as previously described for the related protein, FBP17[21].

Localization (localized) of PSTPIP1 in filaments

14) Confidence 0.70 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2702820 Disease Relevance 0.07 Pain Relevance 0

In this case, pyrin is localized in 100% of specks, but PSTPIP1 is never localized in specks (Figure 9Q–S).

Localization (localized) of PSTPIP1

15) Confidence 0.70 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2702820 Disease Relevance 0.08 Pain Relevance 0

General Comments

This test has worked.